Therapeutic compounds and related methods of use

ABSTRACT

Compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds to treat a disorder, e.g., schizophrenia and cognitive deficit, in a subject are described herein. The compounds disclosed herein include quinoline and quinazoline-containing compounds that modulate striatal-enriched tyrosine phosphatase (STEP) activity.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.Nos. 61/291,544, entitled “Therapeutic Compounds and Related Methods ofUse” filed on Dec. 31, 2009; 61/291,550, entitled “Therapeutic Compoundsand Related Methods of Use” filed on Dec. 31, 2009; and 61/291,554,entitled “Therapeutic Compounds and Related Methods of Use” filed onDec. 31, 2009, all of which are herein incorporated by reference intheir entireties.

BACKGROUND OF INVENTION

Tyrosine phosphorylation of synaptic receptors and signaling moleculesregulates synaptic activity. A number of protein tyrosine phosphatasesspecifically expressed within the brain have been identified, includingSTEP (for STriatal-Enriched tyrosine Phosphatase, also known as PTPN5).Recent evidence suggests that STEP plays an important role in synapticplasticity, for review see (Braithwaite S P. et al., (2006), TrendsNeurosci, 29 (8): 452; Baum M L, et al., (2010), Commun Integr Biol, 3(5): 419) STEP is specifically expressed within neurons of the centralnervous system. As its name indicates, the highest expression level iswithin the striatum. However, more recent work has found that it isexpressed at lower levels in multiple brain regions including theneocortex, amygdala, hippocampus, and embryonic spinal cord.

Four groups of proteins that STEP regulates have been identified: themitogen-activated protein kinases (MAPKs), the tyrosine kinase Fyn, theN-methyl-D-aspartate (NMDA) receptor complex (specifically the NR2Bsubunit) and AMPA receptors (specifically, GluR2, (Zhang Y, et al.,(2008), J Neurosci, 28 (42): 10561)). Three additional new substratesfor STEP have also been recently discovered; proline-rich tyrosinekinase 2 (Pyk2; Xu J, et al., (2010), Abstracts of the Society forNeuroscience Meetings), the fragile X mental retardation protein (FMRP)(Goebel-Goody S M, et al., (2010), Abstracts of the Society forNeuroscience Meetings) and the cell-death mediator Bak (Fox J L, et al.,(2010), EMBO J, 29 (22): 3853). Tyrosine phosphorylation of one memberof the MAPK family, the extracellular signal regulated kinase (ERK), isnecessary for the expression and maintenance of synaptic plasticity inmany brain regions, and disruption of the ERK pathway leads to adisruption of learning and memory. One of the functions of these src andPyk2 kinases is to phosphorylate NMDA receptors, thereby modulatingtheir channel conductance properties and facilitating their movementtoward the surface of neuronal plasma membranes. Pyk2 and Fyn tyrosinekinases are activated by phosphorylation on tyrosine residues. NR2Bphosphorylation on Tyrosine 1452 inhibits the receptor endocytosis. STEPacts as direct or indirect brake of NMDAR mediated signaling by eitherrespectively dephosphorylating NR2B or its associated kinases, Pyk2 andFyn. Activation of AMPA, NMDA receptors and MAPKs are required for theinduction of several forms of long-term potentiation (LTP) and long-termdepression (LTD). Hippocampal LTP is increased in transgenic mice modelof Alzheimer lacking STEP (Zhang Y, et al., (2010), Proc Natl Acad SciUSA, 107 (44): 19014). NR2B and AMPA receptor surface expression isincreased in STEP KO mice. AMPA receptor endocytosis in group Imetabotropic glutamate receptor I (mGluR) mediated LTD is mediated by atyrosine phosphatase. AMPA receptor endocytosis induced by activation ofgroup I mGLuR is blocked in STEP KO mice suggesting that STEP might alsocontrol mGluR mediated LTD.

Compounds that inhibit STEP activity should mimic the effects observedwith the STEP KO and may be useful for treating conditions mediated byabnormal NMDA-receptor (NMDA-Rs) and/or MAP kinase pathway signaling.Both may mediate cognition, learning and memory, neurogenesis, and mayalso affect neuronal plasticity, pain perception, mood and anxiety, andneuroendocrine regulation.

Modulation of NMDA-Rs:

STEP decreases the tyrosine phosphorylation level of NMDA-Rs. Lessphosphorylated NMDA-Rs have lower conductance states and thus will allowless current and fewer ions to pass. The NMDA-Rs will therefore befunctionally less active (Alvestad K M, et al., (2003), J Biol Chem, 278(13): 11020), which can lead to schizophrenic symptoms. Hypofunction ofNMDA-Rs has been liked to schizophrenia. For example, phencyclidine,ketamine, and other noncompetitive antagonists at NMDA-type glutamatereceptors can exacerbate symptoms in patients (Lahti A C, et al.,(1995), Neuropsychopharmacology, 13 (1): 9) and may produce a range ofpsychotic symptoms in volunteers that are similar to those ofschizophrenic patients. NMDA-R hypofunction is also linked to psychosisand drug addiction (Javitt D C and Zukin S R, (1991), Am J Psychiatry,148 (10): 1301). Chronic treatment of atypical antipsychotic clozapineand risperidone in mice result in significant increase ofphosphorylation of ERK, NR2B and Pyk2 on tyrosine residues recognized bySTEP (Carry N C, et al., (2010), Abstracts of the Society forNeuroscience Meetings). Treatment of these anti-psychotics also enhancescAMP and STEP phosphorylation. Since PKA mediated phosphorylation ofSTEP is know to inactivate STEP, these results suggest that STEPinhibition mediates the beneficial effect of antipsychotic drugs. Recentstudies have linked abnormal NMDA-R activity and expression of STEP tothe cognitive decline observed in Alzheimer's disease or transgenic miceexpressing mutant APP (Tg2576 mice) (Snyder E M, et al., (2005), NatNeurosci, 8 (8): 1051; Hynd M R, et al., (2004), J Neurochem, 90 (4):913; Kurup P, et al., (2010), Channels (Austin), 4 (5)). Morespecifically, STEP KO mice are less susceptible to PCP-inducedhyperlocomotion and PCP-induced cognitive deficits in the objectrecognition tasks (Carty N C, et al., (2010), Abstracts of the Societyfor Neuroscience Meetings). Compared to the Tg2576 mice expressing STEP,Tg2576 lacking STEP gene showed rescue in their deficits in hyppocampalLTP and in different behavioral cognitive tasks. Altogether, theseresults suggest that STEP inhibitors might represent a novel class ofdrugs that can treat both positive symptoms and cognitive deficitassociated with schizophrenia.

Medications that modulate glutamatergic neurotransmission via NMDA-Rsmay be also effective in treatment for mood and anxiety disorders.Administration of NMDA-R antagonists has anxiolytic effects in rodentmodels of anxiety (Falls W A, et al., (1992), J Neurosci, 12 (3): 854;Miserendino M J, et al., (1990), Nature, 345 (6277): 716). NMDA-Rsantagonist like ketamine has been shown to be effective indrug-resistant unipolar depression (Machado-Vieira R, et al., (2009),Pharmacol Ther, 123 (2): 143).

Abnormal balance between the activity of NMDA receptors at synaptic(prosurvival linked to ERK activation) and extrasynaptic (proapoptoticlinked to p38 activation) sites has been proposed in cellular and mousemodel of Huntington Disease (HD) (Milnerwood A J, et al., Neuron, 65(2): 178). YAC128 mouse model (containing high number of glutanminerepeat on huntingtin) of HD showed an increased activity ofextrasynaptic NMDA receptors (NR2B subunit) and require p38 andcaspase-6 cleavage activation. In YAC128 mice, NR2B synaptic expressionis associated with high STEP expression and activity and a reduction inNR2B expression and phosphorylation (Gladding C M, et al., (2010),Abstracts of the Society for Neuroscience Meetings). Extrasynaptic NMDAreceptors couple preferentially to excitotoxicity via calpain-mediatedcleavage of STEP and activation of p38 (Xu J, et al., (2009), JNeurosci, 29 (29): 9330). Inhibiting STEP activity might therefore shiftthe balance toward the NMDA receptor/ERK synaptic prosurvival signalingpathway.

Modulation of ERK Pathway:

STEP inhibition may translate into activation of ERK1/2 kinases, forexample, in the central nervous system (CNS). Activation of the ERKpathway in the CNS can mediate neurotrophic pathways involved incellular resilience. ERK signaling directly affects Bak phosphorylationthrough inhibition of STEP to promote cell survival (Fox J L, et al.,(2010), EMBO J, 29 (22): 3853). BDNF and other neurotrophins can blockapoptosis and increase cell survival of different type of CNS neurons invitro and in vivo via stimulation of the ERK pathway. Mood stabilizerseffective in bipolar disorder like valproate and lithium may be potentactivators of ERK activity. This effect on ERK activation is believed tobe responsible for the neurotrophic effects of mood stabilizers observedin vitro or in brains of treated patients with bipolar disorder, forreview see (Engel S R, et al., (2009), Mol Psychiatry, 14 (4): 448; ChenG and Manji H K, (2006), Curr Opin Psychiatry, 19 (3): 313;Machado-Vieira R, et al., (2009), Bipolar Disord, 11 Suppl 2 92). Invivo disruption of STEP activity was shown to activate MAPK pathway,leading to significant rescue from neuronal cell death afterpilocarpine-induced status epilepticus (Choi Y S, et al., (2007), JNeurosci, 27 (11): 2999). Increasing cellular resilience could thereforelimit or reduce neuronal loss in several neurologic disorders. Recentwork has suggested a positive role for STEP inhibition in fragile Xsyndrome (FXS). This disorder results from the mutation of fmr1 genecoding for the fragile X mental retardation protein (FMRP). STEP bindsto FMRP and its expression is dysregulated in FXS. FMR KO mice modeldisplayed audiogenic seizures. FMR KO mice lacking STEP gene show asignificant reduction of these seizures (Goebel-Goody S M, et al.,(2010), Abstracts of the Society for Neuroscience Meetings), suggestingthat STEP modulators might be therapeutic approach for FXS.

Various substituted heterocyclic compounds are disclosed in the art. Forexample, WO 02/062767 discloses quinazoline derivatives; WO 03/000188discloses quinazolines and uses thereof; WO 2005/042501 disclosesnorepinephrine reuptake inhibitors for the treatment of central nervoussystem disorders; WO2006/058201 discloses heterocyclic and bicycliccompounds, compositions and methods; WO 2007/104560 disclosessubstituted 4-amino-quinazoline derivatives as regulators ofmetabotropic glutamate receptors and their use for producing drugs; WO2007/133773 discloses CDKI pathway inhibitors; WO 2008/009078 discloses4,6-DL- and 2,4,6-trisubstituted quinazoline derivatives useful fortreating viral infections; WO 2009/000085 discloses quinoline andquinazoline derivatives useful as modulators of gated ion channels; US2009/0143399 discloses protein kinase inhibitors; and Japan PublicationNumber 2007-084494A discloses substituted bicyclic compounds.

SUMMARY OF INVENTION

Described herein are compounds, pharmaceutical compositions containingthe compounds, and methods of using the compounds to treat a disorder,e.g., schizophrenia or cognitive deficit, in a subject. The compoundsdisclosed herein include quinoline- and quinazoline-containing compoundsthat modulate (e.g., inhibit) the activity of STEP.

The present invention provides therapeutic compounds, pharmaceuticalcomposition comprising said compounds, use of said compounds and methodfor treating or preventing a disorder as described in items 1 to 42below.

-   Item 1. A compound of formula (I):

or a salt thereof,

wherein:

A is CR⁴ or N;

B is aryl, cyclyl or a 5- or 6-membered heteroaryl;

m is 0, 1, 2, 3, 4 or 5;

E is aryl or a 5-membered heteroaryl;

n is 0, 1, 2, 3 or 4;

when E is aryl, n is 0, 1, 2, 3 or 4; and when E is a 5-memberedheteroaryl, n is 0, 1, 2 or 3;

L is NR⁵, S, O or a direct bond;

one of X and Z is N and the other is CH;

p is 0, 1, 2, 3 or 4;

each R¹, R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silyloxyalkynyl,silylalkoxy, silylalkoxyalkyl, —CN, oxo, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(c) or —S(O)_(q)R^(f),each of which is optionally substituted with 1-3 R⁶; wherein two R¹,together with the atoms to which they are attached, may form anoptionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;

R⁴ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁶;

R⁵ is hydrogen; or when m is not 0, R⁵ and one R¹ may be taken togetherwith the atoms to which they are attached to form an optionallysubstituted heteroaryl or heterocyclyl ring;

each R⁶ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(c)or —S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁷;

each R⁷ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′),—C(Y)R^(c) or —S(O)_(q)R^(f), each of which is optionally substitutedwith 1-3 R⁹;

each R⁹ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂,—C(O)OR^(a)—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(c)or —S(O)_(q)R^(f);

Y is O or S;

q is 1 or 2 and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,acyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy orsilylalkoxyalkyl;

wherein when B is phenyl, two R¹ are not taken together to form apyrazole ring; and

when B is phenyl, R² is not

a compound of formula (II):

or a salt thereof,

wherein:

L is CR⁴R⁵, O, C(O), NR⁶C(O) or NR⁷;

A is N;

each X¹, X², X³, X⁴ and X⁵ is independently CH or N, provided that atleast two of X¹, X², X³, X⁴ and X⁵ are N;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3;

R¹ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₅ alkynyl, aryl, heteroaryl,cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl orheterocyclylalkyl, each of which is optionally substituted with 1-5 R⁹;wherein R¹ or R⁹ is optionally taken together with one of R⁴, R⁵, R⁶ orR⁷, and the atoms to which they are attached, to form a cyclyl,heterocyclyl, aryl or heteroaryl ring that is optionally substitutedwith 1-3 R¹⁰;

each R² and R³ is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f); each of which is optionally substituted with 1-3 R¹¹;

each R⁴, R⁵, R⁶ and R⁷ is independently hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl,arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo,haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f);

each R⁹, R¹⁰ and R¹¹ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹²;

wherein, two R⁹, two R¹⁰ or two R¹¹ is optionally taken together withthe atoms to which they are attached to form an optionally substitutedcyclyl, heterocyclyl, aryl or heteroaryl ring;

R¹² is —OR^(d);

Y is O or S;

q is 1 or 2 and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl,heterocyclylalkyl, arylalkyl or heteroarylalkyl and a compound offormula (III):

or a salt thereof,

wherein:

A is CH or N;

L is O, a direct bond or NR⁶;

one of X¹, X², X³, X⁴ and X⁵ is N and the others are CH;

m is 1, or 3;

n is 1, 2, 3 or 4;

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, alkoxyalkyl,hydroxyalkyl, heteroaryl, heteroarylalkyl, arylalkyl, —C(Y)R^(e),cyclyl, cyclylalkyl or heterocyclyl, each of which is optionallysubstituted with 1-3 R⁷;

R² is aryl or heteroaryl, each of which is optionally substituted with1-5 R⁹;

each R³ or R⁴ is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹⁰;

R⁶ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, cyclyl orheterocyclyl, each of which is optionally substituted with 1-3 R¹¹;

each R⁷, R⁹ and R¹⁰ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈alkynyl, aryl, hetero aryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹²;wherein two R⁷, two R⁹ or two R¹⁰ are optionally be taken together withthe atoms to which they are attached to form an optionally substitutedcyclyl, heterocyclyl, aryl or heteroaryl ring;

each R¹¹ and R¹² is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹³;

R¹³ is independently C₁-C₈ alkyl, haloalkyl, halo, heterocyclyl, cyclyl,oxo or —C(Y)NR^(b)R^(b′);

Y is independently O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,acyl, haloalkyl alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, cyclyl,heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl,arylalkyl or heteroarylalkyl;

with proviso R⁹ is not

-   Item 2. The compound according to item 1 represented by general    formula (I) or a salt thereof,

wherein:

A is CR⁴ or N:

B is aryl, cyclyl or a 5- or 6-membered heteroaryl;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2, 3 or 4;

E is aryl or a 5-membered heteroaryl;

when E is aryl, n is 0, 1, 2, 3 or 4; and when E is a 5-memberedheteroaryl, n is 0, 1, 2 or 3;

L is NR⁵, S, O or a direct bond:

one of X and Z is N and the other is CH;

p is 0, 1, 2, 3 or 4;

each R¹, R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silyloxyalkynyl,silylalkoxy, silylalkoxyalkyl, —CN, oxo, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁶;wherein two R¹, together with the atoms to which they are attached, mayform an optionally substituted cyclyl, heterocyclyl, aryl or heteroarylring;

R⁴ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁶;

R⁵ is hydrogen; or when m is not 0, R⁵ and one R¹ may be taken togetherwith the atoms to which they are attached to form an optionallysubstituted heteroaryl or heterocyclyl ring;

each R⁶ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁷;

each R⁷ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—C(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁹;

each R⁹ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f);

Y is O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,acyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy orsilylalkoxyalkyl;

wherein when B is phenyl, two R¹ are not taken together to form apyrazole ring; and

when B is phenyl, R² is not

-   Item 3. The compound according to item 2 represented by general    formula (I) or a salt thereof,

wherein:

A is CH or N;

B is aryl, cyclyl or a 5- or 6-membered heteroaryl;

m is 0, 1, 2, 3 or 4;

E is aryl or a 5-membered heteroaryl;

n is 0, 1 or 2;

when E is aryl, n is 0, 1 or 2 and when E is a 5-membered heteroaryl, nis 0 or 1;

p is 0, 1 or 2;

each R¹, R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, arylalkyl, heterocyclylalkyl, halo,haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silyloxyalkynyl,—CN, oxo, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —SO₂NR^(b)R^(b′), —OR^(d),—SR^(d′), C(Y)R^(c) or —S(O)_(q)R^(f), each of which is optionallysubstituted with 1-3 R⁶; wherein two R¹, together with the atoms towhich they are attached, may form an optionally substituted cyclyl,heterocyclyl, aryl or heteroaryl ring;

each R⁶ is independently C₁-C₈ alkyl, heterocyclyl, heterocyclylalkyl,hydroxyalkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, oxo, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R, —NR^(b)R^(b′), —OR^(d) or—C(Y)R^(e), each of which is optionally substituted with 1-3 R⁷;

each R⁷ is oxo; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,acyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, haloalkyl,dialkylaminoalkyl, hydroxyalkyl or alkoxyalkyl.

-   Item 4. The compound according to item 3 represented by general    formula (I) or a salt thereof,

wherein:

B or two R1 and B are taken together to form a group is phenyl,dihydroindenyl, dihydrobenzoxazinyl, dihydrobenzodioxinyl, chromenyl,tetrahydroquinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,dihydroquinolinyl, quinolyl, isoquinolinyl, tetrahydroquinazolinyl,indolinyl, dihydrobenzothiazolyl, dihydrobenzimidazolyl,dihydrobenzoxazolyl, isoindolinyl, dihydroisobenzofuranyl, benzofuryl,benzothienyl, benzodioxolyl, indolyl, indazolyl, benzoimidazolyl,benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzoxadiazolyl, dihydrocyclopentathiophenyl, tetrahydrobenzothiophenyl,thienyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiadiazolyl,pyrrolyl or pyridyl;

E is phenyl, thienyl or pyrrolyl;

when E is phenyl, n is 1 or 2; and when E is thienyl, n is 0 or 1;

each R¹, R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkynyl, phenyl,thienyl, pyrrolyl, oxadiazolyl, pyridyl, benzodioxolyl, furyl,pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, C₃-C₈ cycloalkyl,piperidyl, pyrrolidinyl, morpholinyl, dioxolanyl, phenylalkyl,thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl,piperidylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl,alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO₂, oxo,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —SO₂NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁶;

each R⁶ is independently C₁-C₈ alkyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, morpholinylalkyl, dialkylaminoalkyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, oxo, —CN, —NO₂, —C(O)OR^(a),—NR^(c)C(Y)R^(c′), —C(Y)NR^(b)R^(b′), —NR^(b)R^(b′), alkoxyalkyl,—OR^(d) or —C(Y)R^(e); and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₅ alkenyl, C₂-C₈ alkynyl,C₃-C₈ cycloalkyl, phenyl, pyridyl, dihydroindenyl, morpholinyl,tetrahydropyranyl, piperidyl, pyrrolidinyl, piperazinyl,thiomorpholinyl, phenylalkyl, thienylalkyl, furylalkyl, pyridylalkyl,tetrahydropyranylalkyl, dihydroindenylalkyl, tetrahydrofurylalkyl,hydroxyalkyl, thiazolylalkyl, pyrazolylalkyl, morpholinylalkyl,pyrrolidinylalkyl, dialkylaminoalkyl, piperidylalkyl,benzodioxolylalkyl, dihydrobenzodioxinylalkyl, benzothienylalkyl, C₃-C₈cycloalkylalkyl, oxazolidinylalkyl, haloalkyl or alkoxyalkyl.

-   Item 5. The compound according to item 3 represented by general    formula (I) or a salt thereof,

wherein:

B or two R1 and B are taken together to form a group is phenyl,dihydroindenyl, dihydrobenzoxazinyl, dihydrobenzodioxinyl, chromenyl,tetrahydroquinoxalinyl, tetrahydroisoquinolyl, tetrahydroquinolinyl,dihydroquinolyl, quinolyl, isoquinolyl, tetrahydroquinazolinyl,indolinyl, dihydrobenzothiazolyl, dihydrobenzimidazolyl,dihydrobenzoxazolyl, isoindolinyl, dihydroisobenzofuranyl, benzofuryl,benzothienyl, benzodioxolyl, indolyl, indazolyl, benzoimidazolyl,benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzoxadiazolyl, dihydrocyclopentathiophenyl, tetrahydrobenzothienyl,thienyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiadiazolyl,pyrrolyl or pyridyl;

E is phenyl, thienyl or pyrrolyl;

when E is phenyl, n is 0, 1 or 2; and when E is thienyl, n is 0 or 1;

each R¹, R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkynyl, phenyl,thienyl, pyrrolyl, oxazolyl, oxadiazolyl, pyridyl, benzodioxolyl, furyl,pyrimidinyl, isoxazolyl, pyrazolyl, C₃-C₈ cycloalkyl, piperidyl,pyrrolidinyl, morpholinyl, dioxolanyl, phenylalkyl,thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl,piperidylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl,alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO₂, oxo,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(b)R^(b′), —NR^(c)C(Y)R^(c′),—OC(O)NR^(b)R^(b′), —SO₂NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁶;

each R⁶ is independently C₁-C₈ alkyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, morpholinylalkyl, dialkylaminoalkyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, oxo, —CN, —NO₂, —C(O)OR^(a),—NR^(c)C(Y)R^(c′), —C(Y)NR^(b)R^(b′), —NR^(b)R^(b′), alkoxyalkyl,—OR^(d) or —C(Y)R^(e), each of which is optionally substituted with 1-3R⁷;

R⁷ is oxo; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₃-C₈ cycloalkyl, phenyl, pyridyl, dihydroindenyl, morpholinyl,tetrahydropyranyl, piperidyl, pyrrolidinyl, piperazinyl,thiomorpholinyl, phenylalkyl, thienylalkyl, furylalkyl, pyridylalkyl,tetrahydropyranylalkyl, dihydroindenylalkyl, tetrahydrofurylalkyl,hydroxyalkyl, thiazolylalkyl, pyrazolylalkyl, morpholinylalkyl,pyrrolidinylalkyl, dialkylaminoalkyl, piperidylalkyl,benzodioxolilalkyl, dihydrobenzodioxiyalkyl, benznylalkyl,benzothienylalkyl, C₃-C₈ cycloalkylalkyl, oxazolidinylalkyl, haloalkyl,or alkoxyalkyl.

-   Item 6. The compound according to item 5 represented by general    formula (I) or a salt thereof,

wherein:

R¹ is C₁-C₈ alkyl, phenyl, thienyl, pyrrolyl, oxazolyl, C₃-C₈cycloalkyl, dioxolanyl, phenylalkyl, halo, haloalkyl, haloalkoxy,alkoxyalkyl, —CN, oxo, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —SO₂NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁶;

R² is C₁-C₈ alkyl, C₂-C₈ alkynyl, phenyl, thienyl, pyridyl,benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C₃-C₈cycloalkyl, pyrrolidinyl, morpholinyl thiomorpholinylalkyl,pyrrolidinylalkyl, morpholinylalkyl, piperiridylalkyl, piperazinylalkyl,halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl,silyloxyalkynyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(b)R^(b′), —OC(O)NR^(b)R^(b′), —OR^(d) or —C(Y)R^(e), each of whichis optionally substituted with 1-3 R⁶;

R³ is C₁-C₈ alkyl, halo, haloalkyl, —NR^(b)R^(b′) or —OR^(d), each ofwhich is optionally substituted with 1-3 R⁶.

-   Item 7. The compound according to item 4 or 6 represented by general    formula (I) or a salt thereof,

wherein:

R¹ is C₁-C₈ alkyl, phenyl, thienyl, pyrrolyl, oxazolyl, C₃-C₈cycloalkyl, dioxolanyl, phenylalkyl, halo, haloalkyl, haloalkoxy,alkoxyalkyl, —CN, oxo, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —SO₂NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f);

R² is C₁-C₈ alkyl, C₂-C₈ alkynyl, phenyl, thienyl, pyridyl,benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C₃-C₈cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl,piperiridinylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl,alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′), —OR^(d),—C(Y)R^(e) or —S(O)_(q)R^(f);

R³ is C₁-C₈ alkyl, halo, haloalkyl, —NR^(b)R^(b′) or —OR^(d).

-   Item 8. The compound according to item 7 represented by general    formula (I) or a salt thereof,

wherein:

B or two R1 and B are taken together to form a group is phenyl,dihydroindenyl, dihydrobenzoxazinyl, dihydrobenzodioxinyl, chromenyl,tetrahydroisoquinolyl, tetrahydroquinolinyl, dihydroquinolyl, quinolyl,tetrahydroquinazolinyl, indolinyl, dihydrobenzothiazolyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, isoindolinyl, benzofuryl,benzothienyl, benzodioxolyl, indolyl, indazolyl, benzoimidazolyl,benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzoxadiazolyl, tetrahydrobenzothienyl, thienyl, thiazolyl, imidazolyl,pyrazolyl, thiadiazolyl or pyridyl:

m is 1, 2, 3 or 4;

R¹ is C₁-C₈ alkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, —CN, oxo,—NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′),—SO₂NR^(b)R^(b′), —OR^(d), or —S(O)_(q)R^(f);

R² is C₁-C₈ alkyl, C₃-C₈ cycloalkyl, thiomorpholinylalkyl,pyrrolidinylalkyl, morpholinylalkyl, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl,silyloxyalkyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(b)R^(b′),—OR^(d), —C(Y)R^(e) or —S(O)_(q)R^(f);

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈ alkynyl,C₃-C₈ cycloalkyl, phenyl, dihydroindenyl, morpholinyl,tetrahydropyranyl, piperidyl, pyrrolidinyl, thiomorpholinyl,phenylalkyl, thienylalkyl, pyridylalkyl, tetrahydropyranylalkyl,dihydroindenylalkyl, tetrahydrofurylalkyl, hydroxyalkyl,morpholinylalkyl, pyrrolidinylalkyl, dialkylaminoalkyl, piperidylalkyl,benzodioxolilalkyl, dihydrobenzodioxinylalkyl, C₃-C₈ cycloalkylalkyl,haloalkyl or alkoxyalkyl.

-   Item 9. The compound according to item 1 represented by general    formula (II) or a salt thereof,

wherein:

L is CR⁴R⁵, O, C(O), NR⁶C(O) or NR⁷;

A is N;

each X¹, X², X³, X⁴ and X⁵ is independently CH or N, provided that atleast two of X¹, X², X³, X⁴, and X⁵ are N;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3;

R¹ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, heteroaryl,cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl orheterocyclylalkyl, each of which is optionally substituted with 1-5 R⁹;wherein R¹ or R⁹ is optionally taken together with one of R⁴, R⁵, R⁶ orR⁷, and the atoms to which they are attached to form a cyclyl,heterocyclyl, aryl or heteroaryl ring that is optionally substitutedwith 1-3 R¹⁰;

each R² and R³ is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹¹;

each R⁴, R⁵, R⁶ and R⁷ is independently hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl,arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo,haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f);

each R⁹, R¹⁰ and R¹¹ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or —S(O)_(q)R^(f),each of which is optionally substituted with 1-3 R¹²; wherein two R⁸,two R⁹, two R¹⁰ or two R¹¹ is optionally taken together with the atomsto which they are attached to form an optionally substituted cyclyl,heterocyclyl, aryl or heteroaryl ring;

R¹² is —OR^(d);

Y is O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently hydrogen,

C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, acyl, cyclyl, heterocyclyl,aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, arylalkyl, orheteroarylalkyl.

-   Item 10. The compound according to item 9 represented by general    formula (II) or a salt thereof,

L is NR⁷;

n is 0, 1 or 2;

p is 0;

R¹ is C₁-C₈ alkyl, aryl or heteroaryl;

each R² and R³ is independently hydrogen, C₁-C₈ alkyl, aryl, halo,heterocyclylalkyl, —NR^(c)C(Y)R^(c), —NR^(b)R^(b′) or —OR^(d), each ofwhich is optionally substituted with 1-3 R¹¹;

R⁷ is hydrogen; and

each R⁹, R¹⁰ and R¹¹ is independently C₁-C₈ alkyl, heterocyclyl, halo,haloalkyl, haloalkoxy, —CN, —C(O)OR^(a), —C(Y)NR^(b)R^(b′), —OR^(d) or—C(Y)R^(c);

Y is O;

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently hydrogen, C₁-C₈ alkyl, cyclyl, heterocyclyl,aryl, or heteroaryl.

-   Item 11. The compound according to item 10 represented by general    formula (II) or a salt thereof,

wherein:

R¹ is C₁-C₈ alkyl, phenyl or benzodioxolyl;

each R² and R³ is independently hydrogen, C₁-C₈ alkyl, phenyl, halo,morholinylalkyl, —NR^(c)C(Y)R^(c), —NR^(b)R^(b′) or —OR^(d);

R⁹ is independently C₁-C₈ alkyl, morpholinyl, tetrahydropyranyl, halo,haloalkyl, haloalkoxy, —CN, —C(O)OR^(a), —C(Y)NR^(b)R^(b′), —OR^(d) or—C(Y)R^(c); and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl,tetrahydropyranyl, phenyl, or pyridyl.

-   Item 12. The compound according to item 10 represented by general    formula (II) or a salt thereof,

wherein:

R¹ is C₁-C₈ alkyl, phenyl or benzodioxolyl;

each R² and R³ is independently hydrogen, C₁-C₈ alkyl, phenyl, halo,morholinylalkyl, —NR^(c)C(Y)R^(c), —NR^(b)R^(b′) or —OR^(d), each ofwhich is optionally substituted with 1-3 R¹¹;

each R⁹, R¹⁰ and R¹¹ is independently C₁-C₈ alkyl, morpholinyl,tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —OR^(d) or —C(Y)R^(e); and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl,tetrahydropyranyl, phenyl, or pyridyl.

-   Item 13. The compound according to item 12 represented by general    formula (II) or a salt thereof, wherein:

R² is C₁-C₈ alkyl, phenyl, halo, morholinylalkyl, —NR^(c)C(Y)R^(c′),—NR^(b)R^(b′) or —OR^(d), each of which is optionally substituted with1-3 R¹¹;

R³ is hydrogen;

R⁹ is halo, haloalkoxy, —CN, —C(O)OR^(a) or —C(Y)NR^(b)R^(b′); and

R¹¹ is C₁-C₈ alkyl, morpholinyl, tetrahydropyranyl, halo, —CN, —OR^(d)or —C(Y)R^(e);

-   Item 14. The compound according to idem 11 or 13 represented by    general formula (II) or a salt thereof, wherein:

R² is C₁-C₈ alkyl, phenyl, halo, morholinylalkyl, —NR^(c)C(Y)R^(c′),—NR^(b)R^(b′) or —OR^(d);

R³ is hydrogen; and

R⁹ is halo, haloalkoxy, —CN, —C(O)OR^(a) or —C(Y)NR^(b)R^(b′).

-   Item 15. The compound according to item 1 represented by general    formula (III) or a salt thereof,

wherein:

A is CH or N;

L is O, a direct bond or NH;

one of X¹, X², X³, X⁴ and X⁵ is N and the others are CH;

m is 1, or 3:

n is 1, 2, 3 or 4;

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, alkoxyalkyl,hydroxyalkyl, heteroaryl, heteroarylalkyl, arylalkyl, —C(Y)R^(e),cyclyl, cyclylalkyl or heterocyclyl, each of which is optionallysubstituted with 1-3 R⁷;

R² is aryl or heteroaryl, each of which is optionally substituted with1-5 R⁹;

each R³ or R⁴ is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d), —C(Y)R^(c) or —S(O)_(q)R^(f),each of which is optionally substituted with 1-3 R¹⁰;

each R⁷, R⁹ and R¹⁰ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹²;wherein two R⁷ or two R⁹ are optionally be taken together with the atomsto which they are attached to form an optionally substituted cyclyl,heterocyclyl, aryl or heteroaryl ring;

R¹² is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹³;

R¹³ is independently C₁-C₈ alkyl, haloalkyl, halo, heterocyclyl, cyclyl,oxo or —C(Y)NR^(b)R^(b′);

Y is or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,acyl, cyclyl, heterocyclyl, aryl, haloalkyl, alkoxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cyclylalkyl,heterocyclylalkyl, arylalkyl or heteroarylalkyl.

-   Item 16. The compound according to item 15 represented by general    formula (III) or a salt thereof,

wherein:

m is 1;

n is 1;

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, heteroaryl,heterocyclyl, arylalkyl, cyclylalkyl, heteroarylalkyl, alkoxyalkyl,hydroxyalkyl or —C(O)R^(e), each of which is optionally substituted with1-3 R⁷;

R² is aryl, heteroaryl or benzofuryl, each of which is optionallysubstituted with 1-5 R⁹;

each R³ or R⁴ is independently hydrogen, C₁-C₈ alkyl, halo, haloalkyl or—OR^(d);

R⁶ is hydrogen or C₁-C₈ alkyl;

each R⁷ and R⁹ is independently C₁-C₈ alkyl, aryl, heteroaryl, halo,haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO₂,—C(O)OR^(a), —C(O)NR^(b)R^(b′), —NR^(b)R^(b′), —OR^(d), —C(O)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹²;

R¹² is independently C₁-C₈ alkyl, oxo, halo, haloalkyl, —CN,—C(O)NR^(b)R^(b′) or —C(O)R^(e) each of which is optionally substitutedwith 1-3 R¹³;

R¹³ is independently C₁-C₈ alkyl, halo or heterocyclyl; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, cyclyl, heterocyclyl, arylalkyl,alkoxyalkyl, heterocyclylalkyl, heteroarylalkyl, alkylaminoalkyl,dialkylaminoalkyl or phenyl.

-   Item 17. The compound according to Item 16 represented by general    formula (III) or a salt thereof,

wherein:

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, alkoxyalkyl,hydroxyalkyl, imidazolyl, pyridylalkyl, phenylalkyl, oxazolylalkyl,thienylalkyl, thiazolidinyl isoindolyl, —C(O)R^(e), dihydroindenyl,C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, piperidyl, morpholinyl,pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionallysubstituted with 1-3 R⁷;

R² is phenyl, naphthyl, benzofuryl, indazolyl, benzothienyl, pyridyl,pyrimidinyl, dihydrobenzodioxinyl, benzodioxolyl, benzoimidazolyl,isoxazolyl, pyrazolyl, indolinyl or benzoisoxazolyl, each of which isoptionally substituted with 1-5 R⁹;

each R³ or R⁴ is independently hydrogen, C₁-C₈ alkyl, halo, haloalkyl or—OR^(d):

R⁶ is hydrogen or C₁-C₈ alkyl;

each R⁷ and R⁹ is independently C₁-C₈ alkyl, phenyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO₂, —C(O)OR^(a),—C(O)NR^(b)R^(b′), —NR^(b)R^(b′), —OR^(d), —C(O)R^(e) or —S(O)_(q)R^(f);and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl,alkoxyalkyl, morholinylalkyl, oxazolidinylalkyl, imidazolylalkyl,tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl,thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl,dihydrobenzoxazinylalkyl, tetrahydrofurylalkyl, tetrahydrofuryl,alkylaminoalkyl, dialkylaminoalkyl or phenyl.

-   Item 18. The compound according to item 16 represented by general    formula (III) or a salt thereof,

wherein:

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, alkoxyalkyl,hydroxyalkyl, imidazolyl, furylalkyl, pyridylalkyl, phenylalkyl,oxazolylalkyl, thienylalkyl, thiazolidinyl, isoindolyl, —C(O)R^(e),dihydroindenyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, piperidyl,morpholinyl, pyrrolidinyl, azetidinyl or piperazinyl, each of which isoptionally substituted with 1-3 R⁷;

R² is phenyl, naphthyl, benzofuryl, indazolyl, benzothienyl, pyridyl,pyrimidinyl, dihydrobenzodioxinyl, benzodioxolyl, benzoimidazolyl,isoxazolyl, pyrazolyl, indolinyl or benzisoxazolyl, each of which isoptionally substituted with 1-5 R⁹;

each R³ or R⁴ is independently hydrogen, C₁-C₈ alkyl, halo, haloalkyl or—OR^(d);

R⁶ is hydrogen or C₁-C₈ alkyl;

each R⁷ and R⁹ is independently C₁-C₈ alkyl, phenyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO₂, —C(O)OR^(a),—C(O)NR^(b)R^(b′), —NR^(b)R^(b′), —OR^(d), —C(O)R^(e) or —S(O)_(q)R^(f),each of which is optionally substituted with 1-3 R¹²;

R¹² is independently C₁-C₈ alkyl, oxo, halo, haloalkyl, —CN,—C(O)NR^(b)R^(b′) or —C(O)R^(e), each of which is optionally substitutedwith 1-3 R¹³;

R¹³ is independently C₁-C₈ alkyl, halo or pyrrolidinyl; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, pyrrolidinyl,piperidyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl,alkoxyalkyl, morpholinylalkyl, oxazolidinylalkyl, imidazolylalkyl,tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl,thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl,dihydrobenzoxazinylalkyl, tetrahydrofurylalkyl, tetrahydrofuryl,alkylaminoalkyl, dialkylaminoalkyl or phenyl.

-   Item 19. The compound according to idem 18 represented by general    formula (III) or a salt thereof,

wherein:

A is N;

R³ is hydrogen, C₁-C₈ alkyl, halo, haloalkyl, or —OR^(d);

R⁴ is hydrogen, C₁-C₈ alkyl, halo, or —OR^(d);

R⁷ is C₁-C₈ alkyl, phenyl, halo, haloalkyl, oxo, —C(O)OR^(a),—C(O)NR^(b)R^(b′) or —OR^(d) each of which is optionally substitutedwith 1-3 R¹²;

R⁹ is C₁-C₈ alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,alkoxyalkyl, —CN, —NO₂, —C(O)NR^(b)R^(b′), —C(O)OR^(a), —NR^(b)R^(b′),—OR^(d), —C(O)R^(e) or —S(O)_(q)R^(f), each of which is optionallysubstituted with 1-3 R¹²; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, pyrrolidinyl,piperidyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl,alkoxyalkyl, morpholinylalkyl, oxazolidinylalkyl, imidazolylalkyl,tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl,thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl,tetrahydrofurylalkyl, dihydrobenzoxazinylalkyl, tetrahydrofuryl,alkylaminoalkyl, dialkylaminoalkyl or phenyl.

-   Item 20. The compound according to item 17 or 19 represented by    general formula (III) or a salt thereof,

wherein:

A is N;

R³ is hydrogen, C₁-C₈ alkyl, halo, haloalkyl, or —OR^(d);

R⁴ is hydrogen, C₁-C₈ alkyl, halo, or —OR^(d);

R⁷ is C₁-C₈ alkyl, phenyl, halo, haloalkyl, oxo, —C(O)OR^(a),—C(O)NR^(b)R^(b′) or —OR^(d);

R⁹ is C₁-C₈ alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,alkoxyalkyl, —CN, —NO₂, —C(O)NR^(b)R^(b′), —C(O)OR^(a), —NR^(b)R^(b′),—OR^(d), —C(O)R^(e) or —S(O)_(q)R^(f); and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, pyrrolidinyl,piperidyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl,alkoxyalkyl, morpholinylalkyl, oxazolidinylalkyl, imidazolylalkyl,tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl,thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl,tetrahydrofurylalkyl, tetrahydrofuryl, dihydrobenzoxazinylalkyl,alkylaminoalkyl, dialkylaminoalkyl or phenyl.

-   Item 21. The compound according to item 20 represented by general    formula (III) or a salt thereof,

wherein:

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, alkoxyalkyl,hydroxyalkyl, imidazolyl, furylalkyl, pyridylalkyl, phenylalkyl,oxazolylalkyl, thienylalkyl, isoindolyl, —C(O)R^(e), dihydroindenyl,C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, piperidyl, morpholinyl,pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionallysubstituted with 1-3 R⁷;

R² is phenyl, which is optionally substituted with 1-5 R⁹; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, pyrrolidinyl, morpholinyl,tetrahydropyranyl, alkoxyalkyl, morpholinylalkyl,tetrahydropyranylalkyl, pyridylalkyl, thiazolylalkyl, pyrrolylalkyl,tetrahydrofuryl, alkylaminoalkyl or phenyl.

-   Item 22. A pharmaceutical composition comprising the compound    according to any one of items 1 to 21 or a salt thereof as an active    ingredient and a pharmaceutically acceptable carrier.-   Item 23. The pharmaceutical composition according to item 2 for    preventing or treating central nervous system diseases.-   Item 24. The pharmaceutical composition according to item 23 for    treating or preventing central nervous system disorders selected    from the group consisting of schizophrenia; refractory, intractable    or chronic schizophrenia; emotional disturbance; psychotic disorder;    mood disorder; bipolar I type disorder; bipolar II type disorder;    depression; endogenous depression; major depression; melancholy and    refractory depression; dysthymic disorder; cyclothymic disorder;    panic attack; panic disorder; agoraphobia; social phobia;    obsessive-compulsive disorder; post-traumatic stress disorder;    generalized anxiety disorder; acute stress disorder; hysteria;    somatization disorder; conversion disorder; pain disorder;    hypochondriasis; factitious disorder; dissociative disorder; sexual    dysfunction; sexual desire disorder; sexual arousal disorder;    erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep    disorder; adjustment disorder; alcohol abuse; alcohol intoxication;    drug addiction; stimulant intoxication; narcotism; anhedonia;    iatrogenic anhedonia; anhedonia of a psychic or mental cause;    anhedonia associated with depression; anhedonia associated with    schizophrenia; delirium; cognitive impairment; cognitive impairment    associated with Alzheimer's disease, Parkinson's disease and other    neurodegenerative diseases; cognitive impairment caused by    Alzheimer's disease; Parkinson's disease and associated    neurodegenerative diseases; cognitive impairment of schizophrenia;    cognitive impairment caused by refractory, intractable or chronic    schizophrenia; vomiting; motion sickness: obesity; migraine; pain    (ache); mental retardation; autism disorder (autism); Tourette's    disorder; tic disorder; attention-deficit/hyperactivity disorder;    conduct disorder; and Down's syndrome.-   Item 25. A process for producing a pharmaceutical composition    comprising mixing a compound of the formula (I), (II), or (III) or a    salt thereof according to any one of items 1 to 21 with a    pharmaceutically acceptable carrier.-   Item 26. Use of a compound of the formula (I), (II) or (III) or a    salt thereof according to any one of items 1 to 21 as a drug.-   Item 27. Use of the compound according to any one of items 1 to 21    represented by general formula (I), (II) or (III) or a salt thereof    as a STEP inhibitor.-   Item 28. A method of treating a disorder that would benefit by the    modulation of STEP (e.g., by activation of inhibition of STEP) in a    subject, the method comprising administering to a compound of    formula (I), (II) or (III) or a salt thereof according to any one of    items 1 to 21.-   Item 29. The method of item 28, wherein the disorder is    schizophrenia.-   Item 30. The method of item 28, wherein the disorder is cognitive    deficit.-   Item 31. The method of item 28, wherein the compound of formula (I),    (II), or (III) is administered in combination with an additional    therapeutic agent.-   Item 32. The method of item 28, wherein the additional therapeutic    agent is an atypical antipsychotic.-   Item 33. The method of item 28, wherein the additional therapeutic    agent is selected from the group consisting of aripiprazole,    clozapine, ziprasidone, risperidone, quetiapine, olanzapine,    amisulpride, asenapine, iloperidone, melperone, paliperidone,    perospirone, sertindole and sulpiride.-   Item 34. The method of item 28, wherein the additional therapeutic    agent is a typical antipsychotic.-   Item 35. The method of item 28, wherein the additional therapeutic    agent is selected from the group consisting of haloperidol,    molindone, loxapine, thioridazine, molindone, thiothixene, pimozide,    fluphenazine, trifluoperazine, mesoridazine, chlorprothixene,    chlorpromazine, perphenazine, triflupromazine and zuclopenthixol.-   Item 36. A kit comprising a composition comprising a compound of    formula (I), (II), or (III) or a salt thereof according to any one    of items 1 to 21 and an acceptable carrier,-   Item 37. A kit comprising a pharmaceutical composition comprising a    compound of formula (I), (II), or (III) or a salt thereof according    to any one of items 1 to 21 and a pharmaceutically acceptable    carrier.-   Item 38. A compound of formula (IV):

wherein:

A is CH, CR⁴ or N;

B is aryl or a 5- or 6-membered heteroaryl:

m is 0, 1, 2, 3, 4 or 5:

E is aryl or a 5-membered heteroaryl;

when E is aryl, n is 1, 2, 3 or 4; and when E is a 5-memberedheteroaryl, n is 0, 1, 2 or 3;

L is NR⁵ or O;

one of X and Z is N and the other is CH;

p is 0, 1, 2, 3 or 4;

each R¹, R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;wherein two R¹, together with the atoms to which they are attached, mayform an optionally substituted cyclyl, heterocyclyl, aryl or heteroarylring;

R⁴ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl,heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;

R⁵ is hydrogen; or when in is not 0, R⁵ and 1 R¹ may be taken togetherwith the atoms to which they are attached to form an optionallysubstituted heteroaryl or heterocyclyl ring;

each R⁶ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f), each of which may be optionally substituted with 1-3R⁷;

each R⁷ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(a), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f);

each Y is independently O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(d), R^(e),R^(e′) and R^(f) is independently selected from hydrogen, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, acyl, aryl, heteroaryl, cyclyl,heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl,halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl,silylalkoxy and silylalkoxyalkyl, each of which may be optionallysubstituted with 1-3 R⁶, wherein R^(b) and R^(b′), together with theatoms to which they are attached, may form an optionally substitutedcyclyl or heterocyclyl ring;

or a pharmaceutically acceptable derivative or prodrug thereof,

wherein when B is phenyl, two R¹ are not taken together to form apyrazole ring;

when B is phenyl, R² is not

and where in the compound is not:

-   Item 39. A compound of formula (IV):

wherein:

A is CH, CR⁴ or N;

B is aryl or a 5-membered heteroaryl;

E is aryl or a 5-membered heteroaryl;

L is NR⁵ or O;

one of X and Z is N and the other is CH;

m is 0, 1, 2, 3, 4 or 5;

n is 1, 2, 3 or 4;

p is, 1, 2, 3 or 4;

each R¹ and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;wherein two R¹, together with the atoms to which they are attached, mayform an optionally substituted cyclyl, heterocyclyl, or aryl ring;

each R² is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl,heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;wherein two R¹, together with the carbons to which they are attached,may form an optionally substituted cyclyl, heterocyclyl, aryl orheteroaryl ring;

R⁴ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl,heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR,—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;

R⁵ is hydrogen; or when m is not 0, R⁵ and 1 R¹ may be taken togetherwith the atoms to which they are attached to form an optionallysubstituted heteroaryl or heterocyclyl ring;

each R⁶ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)(C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f), each of which may be optionally substituted with 1-3R⁷;

each R⁷ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f);

Y is O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl,cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of whichmay be optionally further substituted with 1-3 R⁶, wherein R^(b) andR^(b′), together with the atoms to which they are attached, may form anoptionally substituted cyclyl or heterocyclyl ring;

wherein when 13 is phenyl, two R¹ are not taken together to form apyrazole ring; and

when B is phenyl, R² is not

-   Item 40. A compound of formula (V):

wherein:

L is CR⁴R⁵, O, C(O), NR⁶C(O), or NR⁷;

A is CR⁸, CH or N;

each X¹, X², X³, X⁴ and X⁵ is independently CH or N, provided that atleast two of X¹, X², X², X⁴ and X⁵ are N:

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3;

R¹ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, heteroaryl,cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl orheterocyclylalkyl, each of which may be optionally substituted with 1-5R⁹; wherein R¹ or R⁹ may optionally be taken together with one of R⁴,R⁵, R⁶ or R⁷, and the atoms to which they are attached, to form acyclyl, heterocyclyl, aryl or heteroaryl ring that is optionallysubstituted with 1-3 R¹⁰;

each R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f); each of which is optionally substituted with 1-3 R¹¹;

each R⁴, R⁵, R⁶ and R⁷ is independently H, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl,heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f);

each R⁸, R⁹, R¹⁰ and R¹¹ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl,heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, oxo, thiono, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally further substituted;wherein two R⁸, two R⁹, two R¹⁰ or two R¹¹ may optionally be takentogether with the atoms to which they are attached to form an optionallysubstituted cyclyl, heterocyclyl, aryl or heteroaryl ring;

each Y is independently O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl,cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of whichmay be optionally substituted with 1-3 R⁸,

or a pharmaceutically acceptable derivative or prodrug thereof.

-   Item 41. A compound of formula (VI):

wherein:

A is CR⁵, CH or N;

L is O or NR⁶;

1, 2 or 3 of X¹, X², X³, X⁴ and X⁵ are N and the others are CH;

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3 or 4;

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, cyclyl orheterocyclyl, each of which is optionally substituted with 1-3 R⁷; orwhen L is NR⁶, R¹ or R⁷ may be taken together with R⁶ and the atoms towhich they are attached to form a heterocyclyl or heteroaryl ring thatis optionally substituted with 1-3 R⁸;

R² is aryl or heteroaryl, each of which is optionally substituted with1-5 R⁹;

each R³, R⁴ and R⁵ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclyalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹⁰;

R⁶ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, cyclyl orheterocyclyl, each of which is optionally substituted with 1-3 R¹¹;

each R⁷, R⁸, R⁹ and R¹⁰ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl,heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, oxo, thiono, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹²;wherein two R⁷, two R⁸, two R⁹ or two R¹⁰ may optionally be takentogether with the atoms to which they are attached to form an optionallysubstituted cyclyl, heterocyclyl, aryl or heteroaryl ring;

each R¹¹ and R¹² is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f);

each Y is independently O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl,cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of whichmay be optionally substituted with 1-3 R⁷;

or a pharmaceutically acceptable derivative or prodrug thereof,

wherein when R¹ is cyclopropyl, R⁹ is not:

-   Item 42. A compound of formula (VI):

wherein:

A is CR⁵, CH or N;

L is O or NR⁶;

1, 2 or 3 of X¹, X², X³, X⁴ and X⁵ are N and the others are CH;

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3 or 4;

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, cyclyl orheterocyclyl, each of which is optionally substituted with 1-3 R⁷; orwhen L is NR⁶, R¹ or R⁷ may be taken together with R⁶ and the atoms towhich they are attached to form a heterocyclyl or heteroaryl ring thatis optionally substituted with 1-3 R⁸;

R² is aryl or heteroaryl, each of which is optionally substituted with1-5 R⁹;

each R³, R⁴ and R¹ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹¹;

R⁶ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, cyclyl orheterocyclyl, each of which is optionally substituted with 1-3 R¹¹;

each R⁷, R⁸, R⁹ and R¹⁰ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl,heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, oxo, thiono, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹²;wherein two R⁷, two R⁸, two R⁹ or two R¹⁰ may optionally be takentogether with the atoms to which they are attached to form an optionallysubstituted cyclyl, heterocyclyl, aryl or heteroaryl ring;

each R¹¹ and R¹² is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f);

each Y is independently O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl,cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of whichmay be optionally substituted with 1-3 R⁷;

wherein R⁹ is not:

Compounds of Formula (I)

The following aspects and embodiments relate to compounds of formula(I).

-   Item 2. The compound according to item 1 represented by general    formula (I) or a salt thereof,

wherein:

A is CR⁴ or N;

B is aryl, cyclyl or a 5- or 6-membered heteroaryl;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2, 3 or 4;

E is aryl or a 5-membered heteroaryl;

when E is aryl, n is 0, 1, 2, 3 or 4; and when E is a 5-memberedheteroaryl, n is 0, 1, 2 or 3;

L is NR⁵, S, O or a direct bond;

one of X and Z is N and the other is CH;

p is 0, 1, 2, 3 or 4;

each R¹, R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silyloxyalkynyl,silylalkoxy, silylalkoxyalkyl, —CN, oxo, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁶;wherein two R¹, together with the atoms to which they are attached, mayform an optionally substituted cyclyl, heterocyclyl, aryl or heteroarylring;

R⁴ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁶;

R⁵ is hydrogen; or when m is not 0, R⁵ and one R¹ may be taken togetherwith the atoms to which they are attached to form an optionallysubstituted heteroaryl or heterocyclyl ring;

each R⁶ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁷;

each R⁷ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁹;

each R⁹ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f);

Y is O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,acyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy orsilylalkoxyalkyl;

wherein when B is phenyl, two R¹ are not taken together to form apyrazole ring; and

when B is phenyl, R² is not

-   Item 3. The compound according to item 2 represented by general    formula (I) or a salt thereof,

wherein:

A is CH or N;

B is aryl, cyclyl or a 5- or 6-membered heteroaryl;

m is 0, 1, 2, 3 or 4;

E is aryl or a 5-membered heteroaryl;

n is 0, 1 or 2;

when E is aryl, n is 0, 1 or 2 and when E is a 5-membered heteroaryl, nis 0 or 1;

p is 0, 1 or 2;

each R¹, R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, arylalkyl, heterocyclylalkyl, halo,haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silyloxyalkynyl,—CN, oxo, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —SO₂NR^(b)R^(b′), —OR^(d),—SR^(d′), —C(Y)R^(e) or —S(O)_(q)R^(f), each of which is optionallysubstituted with 1-3 R⁶; wherein two R¹, together with the atoms towhich they are attached, may form an optionally substituted cyclyl,heterocyclyl, aryl or heteroaryl ring;

each R⁶ is independently C₁-C₈ alkyl, heterocyclyl, heterocyclylalkyl,hydroxyalkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, oxo, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OR^(d) or —C(Y)R^(e), each of which is optionally substituted with 1-3R⁷;

each R⁷ is oxo; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,acyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, haloalkyl,dialkylaminoalkyl, hydroxyalkyl or alkoxyalkyl.

-   Item 4. The compound according to item 3 represented by general    formula (I) or a salt thereof,

wherein:

B or two R1 and B are taken together to form a group is phenyl,dihydroindenyl, dihydrobenzoxazinyl, dihydrobenzodioxinyl, chromenyl,tetrahydroquinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,dihydroquinolinyl, quinolyl, isoquinolinyl, tetrahydroquinazolinyl,indolinyl, dihydrobenzothiazolyl, dihydrobenzimidazolyl,dihydrobenzoxazolyl, isoindolinyl, dihydroisobenzofuranyl, benzofuryl,benzothienyl, benzodioxolyl, indolyl, indazolyl, benzoimidazolyl,benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzoxadiazolyl, dihydrocyclopentathiophenyl, tetrahydrobenzothiophenyl,thienyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiadiazolyl,pyrrolyl or pyridyl;

E is phenyl, thienyl or pyrrolyl;

when E is phenyl, n is 1 or 2; and when E is thienyl, n is 0 or 1;

each R¹, R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkynyl, phenyl,thienyl, pyrrolyl, oxadiazolyl, pyridyl, benzodioxolyl, furyl,pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, C₃-C₈ cycloalkyl,piperidyl, pyrrolidinyl, morpholinyl, dioxolanyl, phenylalkyl,thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl,piperidylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl,alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO₂, oxo,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —SO₂NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁶;

each R⁶ is independently C₁-C₈ alkyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, morpholinylalkyl, dialkylaminoalkyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, oxo, —CN, —NO₂, —C(O)OR^(a),—NR^(c)C(Y)R^(c′), —C(Y)NR^(b)R^(b′), —NR^(b)R^(b′), alkoxyalkyl,—OR^(d) or —C(Y)R^(e); and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₃-C₈ cycloalkyl, phenyl, pyridyl, dihydroindenyl, morpholinyl,tetrahydropyranyl, piperidyl, pyrrolidinyl, piperazinyl,thiomorpholinyl, phenylalkyl, thienylalkyl, furylalkyl, pyridylalkyl,tetrahydropyranylalkyl, dihydroindenylalkyl, tetrahydrofurylalkyl,hydroxyalkyl, thiazolylalkyl, pyrazolylalkyl, morpholinylalkyl,pyrrolidinylalkyl, dialkylaminoalkyl, piperidylalkyl,benzodioxolylalkyl, dihydrobenzodioxinylalkyl, benzothienylalkyl, C₃-C₈cycloalkylalkyl, oxazolidinylalkyl, haloalkyl, or alkoxyalkyl.

-   Item 5. The compound according to item 3 represented by general    formula (I) or a salt thereof,

wherein:

B or two R1 and B are taken together to form a group is phenyl,dihydroindenyl, dihydrobenzoxazinyl, dihydrobenzodioxinyl, chromenyl,tetrahydroquinoxalinyl, tetrahydroisoquinolyl, tetrahydroquinolinyl,dihydroquinolyl, quinolyl, isoquinolyl, tetrahydroquinazolinyl,indolinyl, dihydrobenzothiazolyl, dihydrobenzimidazolyl,dihydrobenzoxazolyl, isoindolinyl, dihydroisobenzofuranyl, benzofuryl,benzothienyl, benzodioxolyl, indolyl, indazolyl, benzoimidazolyl,benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzoxadiazolyl, dihydrocyclopentathiophenyl, tetrahydrobenzothienyl,thienyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiadiazolyl,pyrrolyl or pyridyl;

E is phenyl, thienyl or pyrrolyl;

when E is phenyl, n is 0, 1 or 2; and when E is thienyl, n is 0 or 1;

each R¹, R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkynyl, phenyl,thienyl, pyrrolyl, oxazolyl, oxadiazolyl, pyridyl, benzodioxolyl, furyl,pyrimidinyl, isoxazolyl, pyrazolyl, C₃-C₈ cycloalkyl, piperidyl,pyrrolidinyl, morpholinyl, dioxolanyl, phenylalkyl,thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl,piperidylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl,alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO₂, oxo,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(b)R^(b′), —NR^(c)C(Y)R^(c′),O—C(O)NR^(b)R^(b′), SO₂NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁶;

each R⁶ is independently C₁-C₈ alkyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, morpholinylalkyl, dialkylaminoalkyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, oxo, —CN, —NO₂, —C(O)OR^(a),—NR^(c)C(Y)R^(c′), —C(Y)NR^(b)R^(b′), —NR^(b)R^(b′), alkoxyalkyl,—OR^(d) or —C(Y)R^(e), each of which is optionally substituted with 1-3R⁷;

R⁷ is oxo; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₃-C₈ cycloalkyl, phenyl, pyridyl, dihydroindenyl, morpholinyl,tetrahydropyranyl, piperidyl, pyrrolidinyl, piperazinyl,thiomorpholinyl, phenylalkyl, thienylalkyl, furylalkyl, pyridylalkyl,tetrahydropyranylalkyl, dihydroindenylalkyl, tetrahydrofurylalkyl,hydroxyalkyl, thiazolylalkyl, pyrazolylalkyl, morpholinylalkyl,pyrrolidinylalkyl, dialkylaminoalkyl, piperidylalkyl,benzodioxolilalkyl, dihydrobenzodioxinylalkyl, benzothienylalkyl, C₃-C₈cycloalkylalkyl, oxazolidinylalkyl, haloalkyl, or alkoxyalkyl.

-   Item 6. The compound according to item 5 represented by general    formula (I) or a salt thereof,

wherein:

R¹ is C₁-C₈ alkyl, phenyl, thienyl, pyrrolyl, oxazolyl, C₃-C₈cycloalkyl, dioxolanyl, phenylalkyl, halo, haloalkyl, haloalkoxy,alkoxyalkyl, —CN, oxo, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —SO₂NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R⁶;

R² is C₁-C₈ alkyl, C₂-C₈ alkynyl, phenyl, thienyl, pyridyl,benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C₃-C₈cycloalkyl, pyrrolidinyl, morpholinyl, thiomorpholinylalkyl,pyrrolidinylalkyl, morpholinylalkyl, piperiridylalkyl, piperazinylalkyl,halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl,silyloxyalkynyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(b)R^(b′), —OC(O)NR^(b)R^(b′), —OR^(d) or —C(Y)R^(e), each of whichis optionally substituted with 1-3 R⁶;

R³ is C₁-C₈ alkyl, halo, haloalkyl, —NR^(b)R^(b′) or —OR^(d), each ofwhich is optionally substituted with 1-3 R⁶.

-   Item 7. The compound according to item 4 or 6 represented by general    formula (I) or a salt thereof,

wherein:

R¹ is C₁-C₈ alkyl, phenyl, thienyl, pyrrolyl, oxazolyl, C₃-C₈cycloalkyl, dioxolanyl, phenylalkyl, halo, haloalkyl, haloalkoxy,alkoxyalkyl, —CN, oxo, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —SO₂NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f);

R² is C₁-C₈ alkyl, C₂-C₈ alkynyl, phenyl, thienyl, pyridyl,benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C₃-C₈cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl,piperidinylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl,alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′), —OR^(d),—C(Y)R^(e) or —S(O)_(q)R^(f);

R³ is C₁-C₈ alkyl, halo, haloalkyl, —NR^(b)R^(b′) or —OR^(d).

-   Item 8. The compound according to item 7 represented by general    formula (I) or a salt thereof,

wherein:

B or two R1 and B are taken together to form a group is phenyl,dihydroindenyl, dihydrobenzoxazinyl, dihydrobenzodioxinyl, chromenyl,tetrahydroisoquinolyl, tetrahydroquinolinyl, dihydroquinolyl, quinolyl,tetrahydroquinazolinyl, indolinyl, dihydrobenzothiazolyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, isoindolinyl, benzofuryl,benzothienyl, benzodioxolyl, indolyl, indazolyl, benzoimidazolyl,benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzoxadiazolyl, tetrahydrobenzothienyl, thienyl, thiazolyl, imidazolyl,pyrazolyl, thiadiazolyl or pyridyl;

n is 1, 2, 3 or 4;

R¹ is C₁-C₈ alkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, —CN, oxo,—NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′),—SO₂NR^(b)R^(b′), —OR^(d), or —S(O)_(q)R^(f);

R² is C₁-C₈ alkyl, C₃-C₈ cycloalkyl, thiomorpholinylalkyl,pyrrolidinylalkyl, morpholinylalkyl, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl,silyloxyalkyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(b)R^(b′),—OR^(d), —C(Y)R^(e) or —S(O)_(q)R^(f);

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₃-C₈ cycloalkyl, phenyl, dihydroindenyl, morpholinyl,tetrahydropyranyl, piperidyl, pyrrolidinyl, thiomorpholinyl,phenylalkyl, thienylalkyl, pyridylalkyl, tetrahydropyranylalkyl,dihydroindenylalkyl, tetrahydrofurylalkyl, hydroxyalkyl,morpholinylalkyl, pyrrolidinylalkyl, dialkylaminoalkyl, piperidylalkyl,benzodioxolilalkyl, dihydrobenzodioxinylalkyl, C₃-C₈ cycloalkylalkyl,haloalkyl or alkoxyalkyl.

In some embodiments, A is N. In some embodiments, A is CH. In someembodiments, A is CR⁴.

In some embodiments, B is aryl (e.g., phenyl).

In some embodiments, m is 0.

In some embodiments, m is 1. In some embodiments, m is 2. In someembodiments, m is 3.

In some embodiments, R¹ is in the ortho position. In some embodiments,R¹ is in the meta position. In some embodiments, R¹ is in the paraposition.

In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl or tert-butyl). Insome embodiments, R¹ is heteroaryl (e.g., oxazolyl, oxadiazolyl orquinazolinyl).

In some embodiments, R¹ is heteroaryl substituted with 1-3 R⁶ (e.g., 1R⁶).

In some embodiments, R¹ is oxadiazolyl substituted with 1 R⁶. someembodiments, R⁶ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R¹ is heteroaryl substituted with 2 R⁶. In someembodiments, R¹ is quinazolinyl substituted with 2 R⁶. In someembodiments, one R⁶ is halo (e.g., bromo) and the other is heteroaryl(e.g., pyridyl).

In some embodiments, m is 1 and R¹ is halo (e.g., fluoro, chloro orbromo). In some embodiments, m is 2 and each R¹ is halo (e.g., fluoro,chloro or bromo). In some embodiments, m is 3 and each R¹ is halo (e.g.,fluoro, chloro or bromo). In some embodiments, R¹ is haloalkyl (e.g.,trifluoromethyl). In some embodiments, R¹ is haloalkoxy (e.g.,difluoromethoxy or trifluoromethoxy).

In some embodiments, R¹ is haloalkoxy substituted with 1 R⁶. In someembodiments, R¹ is —O—CF₂—R⁶. In some embodiments, R⁶ is—C(Y)NR^(b)R^(b′). In some embodiments, Y is O, R^(b) is hydrogen andR^(b′) is C₁-C₈ alkyl (e.g., methyl). In some embodiments, R¹ is—O—CF₂—CH₂—R⁶. In some embodiments, R⁶ is —OR^(d). In some embodiments,R^(d) is hydrogen. In some embodiments, R^(d) is C₁-C₈ alkyl (e.g.,methyl). In some embodiments, R⁶ is —NR^(b)R^(b′). In some embodiments,R^(b) and R^(b′) are each independently C₁-C₈ alkyl (e.g., R^(b) andR^(b′) are both methyl). In some embodiments, R⁶ is heterocyclyl (e.g.,morpholino).

In some embodiments, R¹ is aminoalkyl. In some embodiments, R¹ is—CH₂NH₂. In some embodiments, R¹ is alkylaminoalkyl. In someembodiments, R¹ is —CH₂NHCH₂CH₂CH₃. In some embodiments, R¹ isdialkylaminoalkyl. In some embodiments, R¹ is —CH₂N(CH(CH₃)₂)₂.

In some embodiments, R¹ is hydroxyalkyl. In some embodiments, R¹ is—CH₂OH.

In some embodiments, R¹ is —CN.

In some embodiments, R¹ is —NO₂.

In some embodiments, R¹ is —C(O)OR^(a). In some embodiments, R^(a) ishydrogen. In some embodiments, R^(a) is C₁-C₈ alkyl (e.g., methyl orethyl).

In some embodiments, R¹ is —NR^(c)C(Y)R^(c′). In some embodiments, oneof R^(c) and R^(c′) is hydrogen and the other is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, R¹ is —OR^(d). In some embodiments, R^(d) ishydrogen. In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl orethyl).

In some embodiments, R¹ is —SO₂NR^(b)R^(b′). In some embodiments, R^(b)and R^(b′) are both hydrogen.

In some embodiments, R¹ is —C(Y)R^(e). In some embodiments, Y is O. Insome embodiments, R^(e) is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R^(e) is heterocyclyl (e.g., pyrrolidinyl, piperidinyl ormorpholino).

In some embodiments, R¹ is —C(Y)NR^(b)R^(b′). In some embodiments, Y isS. In some embodiments, Y is O. In some embodiments, R^(b) and R^(b′)are both hydrogen. In some embodiments, R^(b) is hydrogen. In someembodiments, R^(b) is hydrogen and R^(b′) is aralkyl. In someembodiments, R^(b) is hydrogen and R^(b′) is optionally substitutedbenzyl. In some embodiments, R^(b) is C₁-C₈ alkyl, e.g., methyl, ethyl,C₃ alkyl (e.g., n-propyl or isopropyl), C₄ alkyl (e.g., n-butyl,sec-butyl or tert-butyl), C₅ alkyl (e.g., n-pentyl, isopentyl orpentan-3-yl), C₆ alkyl (e.g., n-hexyl or 3,3-dimethylbutan-2-yl), or C₇alkyl (e.g., n-heptyl or 2-heptyl).

In some embodiments, R^(b′) is bicyclyl (e.g., indanyl). In someembodiments, R^(b′) is heterocyclyl, e.g., a 6-membered heterocyclyl. Insome embodiments, R^(b′) is a 6-membered oxygen-containing heterocyclyl(e.g., tetrahydropyranyl). In some embodiments, R^(b′) is a 6-memberednitrogen-containing heterocyclyl (e.g., piperidinyl).

In some embodiments, R^(b′) is aralkyl. In some embodiments, the alkylis a C₁-C₈ alkyl (e.g., C₁, C₂, C₃ or C₄ alkyl). In some embodiments,the alkyl is a straight-chain alkyl. In some embodiments, the alkyl is abranched alkyl. In some embodiments, the aryl is phenyl. In someembodiments, R^(b′) is benzyl. In some embodiments, R^(b′) isphenylethyl.

In some embodiments, R^(b′) is heteroaralkyl. In some embodiments, thealkyl is a C₁-C₈ alkyl (e.g., C₁, C₂ or C₃ alkyl). In some embodiments,the alkyl is a straight-chain alkyl. In some embodiments, the alkyl is abranched alkyl. In some embodiments, the heteroaryl is pyridyl. In someembodiments, the heteroaryl is furanyl. In some embodiments, theheteroaryl is thiazolyl. In some embodiments, the heteroaryl is thienyl.

In some embodiments, R^(b′) is cyclylalkyl. In some embodiments, thealkyl is a C₁-C₈ alkyl (e.g., C₁ alkyl). In some embodiments, the cyclylgroup is cyclopropyl. In some embodiments, the cyclyl group iscyclopentyl. In some embodiments, the cyclyl group is a bicyclic group.In some embodiments, the bicyclic group is indanyl. In some embodiments,R^(b′) is heterocyclylalkyl. In some embodiments, the alkyl is a C₁-C₈alkyl (e.g., C₁ alkyl). In some embodiments, the heterocyclyl group istetrahydropyranyl.

In some embodiments, R^(b′) is haloalkyl (e.g., fluoroethyl,difluoroethyl, trifluoroethyl or trifluoropropyl).

In some embodiments, R^(b′) is alkoxyalkyl. In some embodiments, thealkyl is a C₁-C₈ alkyl (e.g., C₁, C₂, C₃ or C₄ alkyl). In someembodiments, the alkyl is a straight-chain alkyl. In some embodiments,the alkyl is a branched alkyl. In some embodiments, the alkoxy ismethoxy.

In some embodiments, R^(b) and R^(b′) are each independently C₁-C₈ alkyl(e.g., R^(b) and R^(b′) are both methyl, both ethyl, or both isopropyl).

In some embodiments, two R¹ and B are taken together to form a bicyclicheteroaryl or heterocyclic ring.

In some embodiments, two R¹ and B are taken together to form

In some embodiments, R¹ is halo. In some embodiments, R¹ is at the 6, 7,or 8 position.

In some embodiments, two R¹ and B are taken together to form a groupselected from:

In some embodiments, R² is aryl.

In some embodiments, each R¹ is independently C₁-C₈ alkyl (e.g., each R¹is methyl). In some embodiments, each R¹ is independently halo (e.g.,each R¹ is fluoro or each R¹ is chloro). In some embodiments, one R¹ isfluoro and the other is chloro. In some embodiments, one R¹ is chloroand the other is bromo.

In some embodiments, each R¹ is independently —OR^(d). In someembodiments, each R^(d) is independently C₁-C₈ alkyl (e.g., each R^(d)is methyl).

In some embodiments, one R¹ is halo (e.g., chloro) and the other isC₁-C₈ alkyl (e.g., methyl). In some embodiments, one R¹ is halo (e.g.,fluoro) and the other is heterocyclylalkyl (e.g., —CH₂-heterocyclyl). Insome embodiments, the heterocyclyl is morpholino. In some embodiments,the heterocyclyl is pyrrolidinyl. In some embodiments, the heterocyclylis piperazinyl. In some embodiments, the piperazinyl is substituted with1 R⁶. In some embodiments, R⁶ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R¹ is halo (e.g., fluoro or chloro) and theother is haloalkyl (e.g., trifluoromethyl).

In some embodiments, one R¹ is halo (e.g., chloro) and the other ishaloalkoxy (e.g., difluoromethoxy or trifluoromethoxy).

In some embodiments, one R¹ is halo (e.g., chloro) and the other is—C(O)OR^(a). In some embodiments, R^(a) is hydrogen.

In some embodiments, one R¹ is halo (e.g., fluoro or chloro) and theother is —C(Y)NR^(b)R^(b′). In some embodiments, Y is O. In someembodiments, R^(b) and R^(b′) are both hydrogen. In some embodiments,one of R^(b) and R^(b′) is hydrogen and the other is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, one R¹ is halo (e.g., chloro) and the other is—NR^(c)C(Y)R^(c′). In some embodiments, Y is O. In some embodiments,R^(c) is hydrogen and R^(c′) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R¹ is halo (e.g., fluoro or chloro) and theother is —OR^(d). In some embodiments, R^(d) is hydrogen. In someembodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R¹ is halo (e.g., fluoro or chloro) and theother is —CN.

In some embodiments, one R¹ is halo (e.g., chloro) and the other is—NO₂.

In some embodiments, one R¹ is —C(O)OR^(d) and the other is —NO₂. Insome embodiments, R^(a) is hydrogen.

In some embodiments, one R¹ is —C(O)OR^(a) and the other is —OR^(d). Insome embodiments, each R^(a) and R^(d) is hydrogen.

In some embodiments, one R¹ is —C(Y)NR^(b)R^(b′) and the other ishaloalkyl (e.g., trifluoromethyl). In some embodiments, R^(b) and R^(b′)are both hydrogen.

In some embodiments, one R¹ is —C(Y)NR^(b)R^(b′) and the other ishaloalkoxy (e.g. trifluoromethoxy). In some embodiments, R^(b) andR^(b′) are both hydrogen.

In some embodiments, one R¹ is —C(Y)NR^(b)R^(b′) and the other is—S(O)_(q)R^(f). In some embodiments, R^(b) and R^(b′) are both hydrogen.In some embodiments, R^(f) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R¹ is —C(Y)NR^(b)R^(b′) and the other is —CN.In some embodiments, R^(b) and R^(b′) are both hydrogen.

In some embodiments, one R¹ is —OR^(d) and the other is C₁-C₈ alkyl(e.g., methyl). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, one R¹ is —OR^(d) and the other is haloalkyl (e.g.,trifluoromethyl). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, one R¹ is —OR^(d) and the other is —C(O)OR^(a). Insome embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R^(a) is hydrogen. In some embodiments, R¹ is C₁-C₈ alkyl(e.g., methyl).

In some embodiments, one R¹ is —OR^(d) and the other is—NR^(c)C(O)R^(c′). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g.,methyl). In some embodiments, R^(c) is hydrogen and R^(c′) is C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R¹ is haloalkyl (e.g., trifluoromethyl) and theother is —CN.

In some embodiments, two R¹, together with the atoms to which they areattached, are taken together to form a cyclyl ring (e.g., a substitutedcyclyl ring). In some embodiments, two R¹, together with the atoms towhich they are attached, are taken together to form a heterocyclyl ring(e.g., a substituted heterocyclyl ring). In some embodiments, two R¹,together with the atoms to which they are attached, are taken togetherto form a heteroaryl ring (e.g., a substituted heteroaryl ring).

In some embodiments, two R¹ and ring B are taken together to form agroup selected from:

In some embodiments, R² is aryl.

In some embodiments, each R¹ is independently halo (e.g., all three R¹are fluoro or all three R¹ are chloro).

In some embodiments, two R¹ are independently halo (e.g., both arechloro) and the other is C₁-C₈ alkyl (e.g., methyl). In someembodiments, two R¹ are independently halo (e.g., both are chloro) andthe other is heteroaryl (e.g., pyrrolyl). In some embodiments, two R¹are independently halo (e.g., both are fluoro) and the other is—C(Y)NR^(b)R^(b′) (e.g., —C(O)NH₂). In some embodiments, two R¹ areindependently C₁-C₈ alkyl (e.g., both are methyl) and the other is halo(e.g., chloro or bromo).

In some embodiments, one R¹ is C₁-C₈ alkyl (e.g., methyl), and two R¹,together with the atoms to which they are attached, are taken togetherto form a heterocyclyl ring.

In some embodiments, one R¹ is —OR^(d), and two R¹, together with theatoms to which they are attached, are taken together to form aheterocyclyl ring. In some embodiments, R^(d) is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, three R¹ and ring B are taken together to form agroup selected from:

In some embodiments, B is a 6-membered heteroaryl.

In some embodiments, B is pyridyl. In some embodiments, B is 3-pyridyl.In some embodiments, in is 2. In some embodiments, two R¹, together withthe atoms to which they are attached, are taken together to form an arylring (e.g., a phenyl ring). In some embodiments, m is 3. In someembodiments, one R¹ is —OR^(d), and two R¹, together with the atoms towhich they are attached, are taken together to form an aryl ring (e.g.,a phenyl ring). In some embodiments, R^(d) is hydrogen.

In some embodiments, B is pyrazolyl. In some embodiments, m is 2. Insome embodiments, two R¹, together with the atoms to which they areattached, are taken together to form a cyclyl ring (e.g., a cyclohexylring).

In some embodiments, B is selected from:

In some embodiments, B is a 5-membered heteroaryl (e.g., pyrazolyl).

In some embodiments, m is 1.

In some embodiments, R¹ is aryl (e.g., phenyl).

In some embodiments, R¹ is phenyl substituted with 1 R⁶.

In some embodiments, R⁶ is halo (e.g., chloro). In some embodiments, R¹is selected from:

In some embodiments, m is 2.

In some embodiments, one R¹ is C₁-C₈ alkyl (e.g., methyl) and the otheris aryl (e.g., phenyl). In some embodiments, the aryl is phenylsubstituted with 1 R⁶. In some embodiments, R⁶ is halo (e.g., chloro).In some embodiments, R¹ is:

In some embodiments, B is thienyl. In some embodiments, B is selectedfrom:

In some embodiments, m is 1. In some embodiments, in is 2. In someembodiments m is 2 and two R¹, together with the atoms to which they areattached, form an optionally substituted cyclyl, heterocyclyl, aryl orheteroaryl ring

In some embodiments, R¹ is —C(O)OR^(a). In some embodiments, R^(a) isC₁-C₈ alkyl (e.g., ethyl).

In some embodiments, R¹ is —C(Y)NR^(b)R^(b′). In some embodiments, Y isO. In some embodiments, R^(b) and R^(b′) are both hydrogen.

In some embodiments, m is 2.

In some embodiments, one R¹ is C₁-C₈ alkyl (e.g., methyl) and the otheris —C(Y)NR^(b)R^(b′). In some embodiments, Y is O. In some embodiments,R^(h) and R^(b′) are both hydrogen.

In some embodiments, B is thiazolyl.

In some embodiments, in is 1.

In some embodiments, R¹ is aryl (e.g., phenyl).

In some embodiments, m is 2.

In some embodiments, two R¹, together with the atoms to which they areattached, form an aryl ring. In some embodiments, the aryl ring issubstituted with —C(Y)R^(e). In some embodiments, Y is O. In someembodiments, R^(e) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, B is:

In some embodiments, B is:

In some embodiments, E is aryl (e.g., phenyl).

In some embodiments, n is 1.

In some embodiments, R² is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R² is C₁-C₈ alkyl substituted with 1-3 R⁶. In someembodiments, R² is C₁ alkyl substituted with 1 R⁶.

In some embodiments, R⁶ is —NR^(b)R^(b′). In some embodiments, R^(b) andR^(b′) are each independently C₁-C₈ alkyl (e.g., R^(b) and R^(b′) areboth methyl, or R^(b) and R^(b′) are both ethyl). In some embodiments,one of R^(b) and R^(b′) is hydrogen and the other is haloalkyl (e.g.,trifluoroethyl).

In some embodiments, R⁶ is —OR^(d). In some embodiments, R^(d) is cyclyl(e.g., cyclopentyl). In some embodiments, R^(d) is heterocyclylalkyl(e.g., —CH₂-tetrahydropyranyl).

In some embodiments, R² is C₂ alkyl substituted with 1 R⁶.

In some embodiments, R⁶ is —C(Y)NR^(b)R^(b′). In some embodiments, Y isO. In some embodiments, R^(b) and R^(b′) are both hydrogen. In someembodiments, R^(b) and R^(b′) are each independently C₁-C₈ alkyl (e.g.,R^(b) and R^(b′) are both methyl). In some embodiments, one of R^(b) andR^(b′) is hydrogen and the other is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R⁶ is —C(Y)R^(e). In some embodiments, Y is O. Insome embodiments, R^(e) is heterocyclyl (e.g., morpholino orthiomorpholino). In some embodiments, R^(e) is thiomorpholinosubstituted with 2 R⁷. In some embodiments, each R⁷ is oxo. In someembodiments, R^(e) is:

In some embodiments, R² is C₃ alkyl substituted with 1 R⁶.

In some embodiments, R⁶ is —C(Y)NR^(b)R^(b′). In some embodiments, Y isO. In some embodiments, R^(b) and R^(b′) are both hydrogen. In someembodiments, R^(b) and R^(b′) are each independently C₁-C₈ alkyl (e.g.,R^(b) and R^(b′) are both methyl). In some embodiments, one of R^(b) andR^(b′) is hydrogen and the other is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R⁶ is —NR^(c)C(Y)R^(c′). In some embodiments, Y isO. In some embodiments, R^(c) and R^(c′) are each independently C₁-C₈alkyl (e.g., R^(c) and R^(c′) are both methyl).

In some embodiments, R⁶ is —OR^(d). In some embodiments, R^(d) ishydrogen. In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R⁶ is silyloxy (e.g., tert-butyldimethylsilyloxy).

In some embodiments, R⁶ is —C(Y)R^(c). In some embodiments, Y is O. Insome embodiments, R^(e) is heterocyclyl (e.g., morpholino).

In some embodiments, R² is C₂-C₈ alkynyl. In some embodiments, R² isC₂-C₈ alkynyl substituted with 1 R⁶ (e.g., C₃ alkynyl substituted with 1R⁶). In some embodiments, R² is —C≡C—CH₂—R⁶. In some embodiments, R⁶ is—NR^(b)R^(b′). In some embodiments, R^(b) and R^(b′) are eachindependently C₁-C₈ alkyl (e.g., R^(b) and R^(b′) are both methyl). Insome embodiments, R⁶ is —OR^(d). In some embodiments, R^(d) is hydrogen.In some embodiments, R⁶ is silyloxy (e.g., tert-butyldimethylsilyloxy).In some embodiments, R⁶ is heterocyclyl (e.g., morpholino orthiomorpholino). In some embodiments, R⁶ is thiomorpholino substitutedwith 2 R⁷. In some embodiments, each R⁷ is oxo. In some embodiments, R⁶is:

In some embodiments, R² is aryl (e.g., phenyl). In some embodiments, R²is unsubstituted phenyl.

In some embodiments, R² is phenyl substituted with 1 R⁶.

In some embodiments, R⁶ is heterocyclylalkyl (e.g., —CH₂-morpholino). Insome embodiments, R⁶ is haloalkyl (e.g., trifluoromethyl). In someembodiments, R⁶ is —CN. In some embodiments. R⁶ is —OR^(d). In someembodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl). In some embodiments,R⁶ is —C(Y)R^(c). In some embodiments, Y is O. In some embodiments,R^(e) is heterocyclyl (e.g., morpholino).

In some embodiments, R² is phenyl substituted with 2 R⁶.

In some embodiments, each R⁶ is independently —OR^(d). In someembodiments, each R^(d) is C₁-C₈ alkyl (e.g., methyl). In someembodiments, one R⁶ is halo (e.g., fluoro) and the other is C₁-C₈ alkyl(e.g., methyl). In some embodiments, one R⁶ is —C(O)OR^(a) and the otheris —OR^(d). In some embodiments, R^(a) and R^(d) are each independentlyC₁-C₈ alkyl (e.g., R^(a) and R^(d) are both methyl).

In some embodiments, R² is heteroaryl.

In some embodiments, R² is isoxazolyl. In some embodiments, R² isisoxazolyl substituted with 2 R⁶. In some embodiments, each R⁶ isindependently C₁-C₈ alkyl (e.g., R⁶ is methyl),

In some embodiments, R² is pyrazolyl. In some embodiments, R² ispyrazolyl substituted with 1 R⁶. In some embodiments, R⁶ is C₁-C₈ alkyl(e.g., methyl).

In some embodiments, R² is pyridyl. In some embodiments, R² isunsubstituted pyridyl. In some embodiments, R¹ is pyridyl substitutedwith 1 R⁶. In some embodiments, R⁶ is halo (e.g., fluoro). In someembodiments, R⁶ is —NR^(b)R^(b′). In some embodiments, R^(b) and R^(b′)are each hydrogen. In some embodiments, R⁶ is —OR^(d). In someembodiments, R^(d) is hydrogen. In some embodiments, R^(d) is C₁-C₈alkyl (e.g., methyl). In some embodiments, R⁶ is heterocyclyl (e.g.,morpholino or piperazinyl). In some embodiments, R⁶ is piperazinylsubstituted with 1 R⁷. In some embodiments, R⁷ is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, R² is pyrimidinyl.

In some embodiments, R² is pyridazinyl.

In some embodiments, R² is cyclyl (e.g., cyclopropyl).

In some embodiments, R² is heterocyclyl (e.g., morpholino orpyrrolidinyl).

In some embodiments, R² is aralkyl (e.g., benzyl).

In some embodiments, R² is heterocyclylalkyl. In some embodiments, thealkyl is C₁ alkyl. In some embodiments, the alkyl is C₂ alkyl. In someembodiments, the alkyl is C₃ alkyl. In some embodiments, theheterocyclyl is piperidinyl. In some embodiments, the heterocyclyl ispiperazinyl. In some embodiments, the heterocyclyl is piperazinylsubstituted with 1 R⁶. In some embodiments, R⁶ is C₁-C₈ alkyl (e.g.,methyl). In some embodiments, the heterocyclyl is pyrrolidinyl. In someembodiments, the heterocyclyl is morpholino. In some embodiments, theheterocyclyl is thiomorpholino. In some embodiments, the heterocyclyl isthiomorpholino substituted with 2 R⁶. In some embodiments, each R⁶ isoxo. In some embodiments, the heterocyclyl is:

In some embodiments, R² is halo (e.g., fluoro, chloro, bromo or iodo).

In some embodiments, R² is haloalkyl (e.g., trifluoromethyl).

In some embodiments, R² is haloalkoxy (e.g., trifluoromethoxy).

In some embodiments, R² is —CN.

In some embodiments, R² is —NO₂.

In some embodiments, R² is —C(O)OR^(a). In some embodiments, R^(a) ishydrogen. In some embodiments, R^(a) is C₁-C₈, alkyl (e.g., methyl).

In some embodiments, R² is —C(Y)NR^(b)R^(b′). In some embodiments, Y isO. In some embodiments, R^(b) and R^(b′) are each hydrogen. In someembodiments, R^(b) and R^(b′) are each independently C₁-C₈ alkyl (e.g.,R^(b) and R^(b′) are both methyl). In some embodiments, one of R^(b) andR^(b′) is hydrogen and the other is C₁-C₈ alkyl (e.g., methyl or ethyl).In some embodiments, one of R^(b) and R^(b′) is hydrogen and the otheris heterocyclylalkyl (e.g., —CH₂—CH₂-morpholino). In some embodiments,one of R^(b) and R^(b′) is hydrogen and the other is haloalkyl (e.g.,trifluoroethyl).

In some embodiments, R² is —NR^(b)R^(b′). In some embodiments, R^(b) andR^(b′) are both hydrogen. In some embodiments, R^(b) and R^(b′) are eachindependently C₁-C₈ alkyl (e.g., R^(b) and R^(b′) are both methyl). Insome embodiments, one of R^(b) and R^(b′) is hydrogen and the other isC₁-C₈ alkyl (e.g., methyl). In some embodiments, one of R^(b) and R^(b′)is hydrogen and the other is heterocyclyl (e.g., tetrahydropyranyl). Insome embodiments, one of R^(b) and R^(b′) is hydrogen and the other isheterocyclylalkyl. In some embodiments, the alkyl is C₁ alkyl. In someembodiments, the alkyl is C₂ alkyl. In some embodiments, the alkyl is C₃alkyl. In some embodiments, the heterocyclyl is morpholino. In someembodiments, the heterocyclyl is pyrrolidinyl. In some embodiments, theheterocyclyl is tetrahydrofuranyl. In some embodiments, the heterocyclylis tetrahydropyranyl. In some embodiments, one of R^(b) and R^(b′) ishydrogen and the other is hydroxyalkyl. In some embodiments, the alkylis C₂ alkyl. In some embodiments, one of R^(b) and R^(b′) is hydrogenand the other is alkoxyalkyl. In some embodiments, the alkyl is C₂alkyl. In some embodiments, the alkyl is C₃ alkyl. In some embodiments,the alkoxy is methoxy. In some embodiments, one of R^(b) and R^(b′) ishydrogen and the other is —C(Y)R^(e). In some embodiments, Y is O. Insome embodiments, R^(e) is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R^(e) is heterocyclyl. In some embodiments, R^(e) istetrahydropyranyl.

In some embodiments, R² is —OR^(d).

In some embodiments, R^(d) is hydrogen. In some embodiments, R^(d) isC₁-C₈ alkyl (e.g., methyl).

In some embodiments, R¹ is ethyl. In some embodiments, R^(d) is C₃ alkyl(e.g., isopropyl or n-propyl). In some embodiments, R^(d) is optionallysubstituted heteroaralkyl. In some embodiments, R^(d) is optionallysubstituted pyrindinalkyl.

In some embodiments, R^(d) is n-propyl. In some embodiments, R^(d) iscyclyl (e.g., cyclopentyl).

In some embodiments, R^(d) is heteroaralkyl (e.g., —CH₂-pyridyl).

In some embodiments, R^(d) is heterocyclylalkyl. In some embodiments,the alkyl is C₁ alkyl. In some embodiments, the alkyl is C₂ alkyl. Insome embodiments, the alkyl is C₃ alkyl. In some embodiments, the alkylis C₄ alkyl. In some embodiments, the heterocyclyl is morpholino. Insome embodiments, the heterocyclyl is piperidyl. In some embodiments,the heterocyclyl is tetrahydrofuranyl. In some embodiments, R^(d) iscyclylalkyl (e.g., —CH₂-cyclobutyl).

In some embodiments, R^(d) is alkoxyalkyl. In some embodiments, thealkyl is C₂ alkyl. In some embodiments, the alkyl is C₃ alkyl. In someembodiments, the alkoxy is methoxy.

In some embodiments, R^(d) is dialkylaminoalkyl. In some embodiments,the alkyl is C₂ alkyl. In some embodiments, the alkyl is C₃ alkyl. Insome embodiments, the dialkylamino is dimethylamino.

In some embodiments, R² is —C(Y)R^(e). In some embodiments, Y is O. Insome embodiments, R^(e) is heterocyclyl. In some embodiments, R^(e) ispiperidyl. In some embodiments, R^(e) is pyrrolidinyl. In someembodiments, R^(e) is piperazinyl. In some embodiments, R^(e) ismorpholino. In some embodiments, R^(e) is thiomorpholino.

In some embodiments, n is 2.

In some embodiments, each R² is independently halo (e.g., each R² ischloro).

In some embodiments, each R² is independently —OR^(d).

In some embodiments, each R^(d) is C₁-C₈ alkyl.

In some embodiments, each R² is methoxy. In some embodiments, one R² ismethoxy and the other is ethoxy. In some embodiments, one R² is methoxyand the other is propoxy. In some embodiments, one R² is methoxy and theother is isopropoxy.

In some embodiments, one R² is methoxy and the other is ethoxysubstituted with 1 R⁶. In some embodiments, R⁶ is —NR^(b)R^(b′). In someembodiments, R^(b) and R^(b′) are each independently C₁-C₈ alkyl (e.g.,R^(b) and R^(b′) are both methyl). In some embodiments, R⁶ is —OR^(d).In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R² is methoxy and the other is propoxysubstituted with 1 R⁶. In some embodiments, R⁶ is —OR^(d). In someembodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R² is —OR^(d) and the other is C₁-C₈ alkyl(e.g., methyl). In some embodiments, R² is C₁-C₈ alkyl (e.g., methyl orethyl).

In some embodiments, one R² is —OR^(d) and the other is halo (e.g.,chloro). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R² is —OR^(d) and the other is —CN. In someembodiments, R^(d) is C₁-C₈ alkyl (e.g. methyl).

In some embodiments, one R² is —OR^(d) and the other is —C(O)OR^(a). Insome embodiments, R^(d) and R^(a) are both hydrogen.

In some embodiments, one R² is —OR^(d) and the other is C₁-C₈ alkyl(e.g., methyl). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, one R² is —OR^(d) and the other is —C(Y)R^(e). Insome embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl). In someembodiments, Y is O. In some embodiments, R^(e) is heterocyclyl (e.g.,morpholino).

In some embodiments, one R² is halo (e.g., chloro or bromo) and theother is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R² is C₁-C₈ alkyl (e.g., methyl) and the otheris —CN.

In some embodiments, one R² is C₁-C₈ alkyl (e.g., methyl) and the otheris heteroaryl (e.g., pyridyl). In some embodiments, the pyridyl issubstituted with 1 R⁶. In some embodiments, R⁶ is —OR^(d). In someembodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R² is C₁-C₈ alkyl (e.g., methyl) and the otheris heterocyclylalkyl (e.g., —CH₂-morpholino).

In some embodiments, p is 0.

In some embodiments, p is 1.

In some embodiments, R³ is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R³ is halo (e.g., chloro). In some embodiments, R³ ishaloalkyl (e.g., trifluoromethyl). In some embodiments R³ is oxo.

In some embodiments, R³ is —OR^(d). In some embodiments, R^(d) ishydrogen. In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R³ is —NR^(b)R^(b′). In some embodiments, R^(b) andR^(b′) are both hydrogen. In some embodiments, one of R^(b) and R^(b′)is hydrogen and the other is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R³ is heterocyclyl (e.g., piperazinyl). In someembodiments, R³ is piperazinyl substituted with 1 R⁶. In someembodiments, R⁶ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, E is a 5-membered heteroaryl ring.

In some embodiments, E is a thiophene ring.

In some embodiments, E is a pyrrole ring.

In some embodiments, n is 1. In some embodiments, R² is C₁-C₈ alkyl(e.g., methyl). In some embodiments, E is an N-methylpyrrole ring.

In some embodiments, L is NR⁵. In some embodiments, R⁵ is hydrogen.

In some embodiments, L is O.

In some embodiments, the compound is:

In some embodiments, R² is C₁-C₄ alkoxy. In some embodiments, R² ishalo. In some embodiments, R¹ is —C(Y)NR^(b)R^(b′).

In some embodiments, the compound is:

In some embodiments, R² is C₁-C₄ alkoxy. In some embodiments, R² ishalo. In some embodiments, R¹ is —C(Y)NR^(b)R^(b′).

In some embodiments,

In some embodiments,

In some embodiments, L is NH, and

is selected from

In some embodiments R⁶ is halo.

In some embodiments, the compound is:

In some embodiments, R¹ is —C(Y)NR^(b)R^(b′). In some embodiments, R¹ ishalo. In some embodiments, R² is C₁-C₄ alkoxy. In some embodiments, R²is halo. In some embodiments, m is 2 and two R¹ are 3,4-dichloro;3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro,4-fluoro; or3-chloro,5-fluoro. In some embodiments, R² is —-C(O)NR^(b)R^(b′) and R³is H. In some embodiments, R^(b) and R^(b′) are H. In some embodiments,R^(b) and R^(b′) are independently C₁-C₄ alkyl or halo-substituted C₁-C₄alkyl. In some embodiments, R^(b) is methyl and R^(b′) istrifluoroethyl. In some embodiments, R¹ is C₁-C₄ alkoxy orhalo-substituted C₁-C₄ alkoxy. In some embodiments, n and p are zero.

In some embodiments, the compound is:

In some embodiments, R¹ is —C(Y)NR^(b)R^(b′). In some embodiments, R¹ ishalo. In some embodiments, R² is C₁-C₄ alkoxy. In some embodiments, R²is halo. In some embodiments, m is 2 and two R¹ are 3,4-dichloro;3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro,4-fluoro; or3-chloro,5-fluoro. In some embodiments, R² is —C(O)NR^(b)R^(b′) and R³is H. In some embodiments, R^(b) and R^(b′) are H. In some embodiments,R^(b) and R^(b′) are independently C₁-C₄ alkyl or halo-substituted C₁-C₄alkyl. In some embodiments, R^(b) is methyl and R^(b′) istrifluoroethyl. In some embodiments, R¹ is C₁-C₄ alkoxy orhalo-substituted C₁-C₄ alkoxy. In some embodiments, n and p are zero.

In some embodiments, the compound is:

In some embodiments, R¹ is —C(Y)NR^(b)R^(b′). In some embodiments, R¹ ishalo. In some embodiments, R² is C₁-C₄ alkoxy. In some embodiments, R²is halo. In some embodiments, in is 2 and two R¹ are 3,4-dichloro;3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro,4-fluoro; or3-chloro,5-fluoro. In some embodiments, R² is —C(O)NR^(b)R^(b′) and R³is H. In some embodiments, R^(b) and R^(b′) are H. In some embodiments,R^(b) and R^(b′) are independently C₁-C₄ alkyl or halo-substituted C₁-C₄alkyl. In some embodiments, R^(b) is methyl and R^(b′) istrifluoroethyl. In some embodiments, R¹ is C₁-C₄ alkoxy orhalo-substituted C₁-C₄ alkoxy. In some embodiments, n and p are zero.

In some embodiments, the compound is:

In some embodiments, R¹ is —C(Y)NR^(b)R^(b′). In some embodiments, R¹ ishalo. In some embodiments, R² is C₁-C₄ alkoxy. In some embodiments, R²is halo. In some embodiments, m is 2 and two R¹ are 3,4-dichloro;3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro,4-fluoro; or3-chloro,5-fluoro. In some embodiments, R² is —C(O)NR^(b)R^(b′) and R³is H. In some embodiments, R^(b) and R^(b′) are H. In some embodiments,R^(b) and R^(b′) are independently C₁-C₄ alkyl or halo-substituted C₁-C₄alkyl. In some embodiments, R^(b) is methyl and R^(b′) istrifluoroethyl. In some embodiments, R¹ is C₁-C₄ alkoxy orhalo-substituted C₁-C₄ alkoxy. In some embodiments, n and p are zero.

Compounds of Formula (II)

The following aspects and embodiments relate to compounds of formula(II).

-   Item 9. The compound according to item 1 represented by general    formula (II) or a salt thereof,

wherein:

L is CR⁴R⁵, O, C(O), NR⁶C(O) or NR⁷;

A is N;

each X¹, X², X³, X and X⁵ is independently CH or N, provided that atleast two of X¹, X², X³, X⁴ and X⁵ are N;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3

R¹ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, heteroaryl,cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl orheterocyclylalkyl, each of which is optionally substituted with 1-5 R⁹;wherein R¹ or R⁹ is optionally taken together with one of R⁴, R⁵, R⁶ orR⁷, and the atoms to which they are attached to form a cyclyl,heterocyclyl, aryl or heteroaryl ring that is optionally substitutedwith 1-3 R¹⁰;

each R² and R³ is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹¹;

each R⁴, R⁵, R⁶ and R⁷ is independently hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl,arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo,haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f);

each R⁹, R¹⁰ and R¹¹ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂, —C(O)OR, —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹²;wherein two R⁸, two R⁹, two R¹⁰ or two R¹¹ is optionally taken togetherwith the atoms to which they are attached to form an optionallysubstituted cyclyl, heterocyclyl, aryl or heteroaryl ring;

R¹² is —OR^(d);

Y is O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(d), R^(d′), R^(e), R^(e′) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl,heterocyclylalkyl, arylalkyl, or heteroarylalkyl.

-   Item 10. The compound according to item 9 represented by general    formula (II) or a salt thereof,

L is NR⁷;

n is 0, 1 or 2;

p is 0;

R¹ is C₁-C₈ alkyl, aryl or heteroaryl;

each R² and R³ is independently hydrogen, C₁-C₈ alkyl, aryl, halo,heterocyclylalkyl, —NR^(c)C(Y)R^(c), —NR^(b)R^(b′) or —OR^(d), each ofwhich is optionally substituted with 1-3 R¹¹;

R⁷ is hydrogen; and

each R⁹, R¹⁰ and R¹¹ is independently C₁-C₈ alkyl, heterocyclyl, halo,haloalkyl, haloalkoxy, —CN, —C(O)OR^(a), —C(Y)NR^(b)R^(b′), —OR^(d) or—C(Y)R^(e);

Y is O;

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently hydrogen, C₁-C₈ alkyl, cyclyl, heterocyclyl,aryl or heteroaryl.

-   Item 11. The compound according to item 10 represented by general    formula (II) or a salt thereof,

wherein:

R¹ is C₁-C₈ alkyl, phenyl or benzodioxolyl;

each R² and R³ is independently hydrogen, C₁-C₈ alkyl, phenyl, halo,morholinylalkyl, —NR^(c)C(Y)R^(c), —NR^(b)R^(b′) or —OR^(d);

R⁹ is independently C₁-C₈ alkyl, morpholinyl, tetrahydropyranyl, halo,haloalkyl, haloalkoxy, —CN, —C(O)OR^(a), —C(Y)NR^(b)R^(b′), —OR^(d) or—C(Y)R^(e); and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl,tetrahydropyranyl, phenyl or pyridyl.

-   Item 12. The compound according to item 10 represented by general    formula (II) or a salt thereof,

wherein:

R¹ is C₁-C₈ alkyl, phenyl or benzodioxolyl;

each R² and R³ is independently hydrogen, C₁-C₈ alkyl, phenyl, halo,morholinylalkyl, —NR^(c)C(Y)R^(c), —NR^(b)R^(b′) or —OR^(d), each ofwhich is optionally substituted with 1-3 R¹¹;

each R⁹, R¹⁰ and R¹¹ is independently C₁-C₈ alkyl, morpholinyl,tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —OR^(d) or —C(Y)R^(e); and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl,tetrahydropyranyl, phenyl, or pyridyl.

-   Item 13. The compound according to item 12 represented by general    formula (II) or a salt thereof, wherein:

R² is C₁-C₈ alkyl, phenyl, halo, morholinylalkyl, —NR^(c)C(Y)R^(c′),—NR^(b)R^(b′) or —OR^(d), each of which is optionally substituted with1-3 R¹¹;

R³ is hydrogen;

R⁹ is halo, haloalkoxy, —CN, —C(O)OR^(a) or —C(Y)NR^(b)R^(b′); and

R¹¹ is C₁-C₈ alkyl, morpholinyl, tetrahydropyranyl, halo, —CN, —OR^(d)or —C(Y)R^(e);

-   Item 14. The compound according to item 11 or 13 represented by    general formula (II) or a salt thereof, wherein:

R² is C₁-C₈ alkyl, phenyl, halo, morholinylalkyl, —NR^(c)C(Y)R^(c′),—NR^(b)R^(b′) or —OR^(d);

R³ is hydrogen; and

R⁹ is halo, haloalkoxy, —CN, —C(O)OR^(a) or —C(Y)NR^(b)R^(b′).

In some embodiments, A is CH. In some embodiments, A is N.

In some embodiments, L is NR⁷. In some embodiments, R⁷ is H.

In some embodiments, R¹ is aryl (e.g., phenyl).

In some embodiments, R¹ is phenyl substituted with 1 R⁹. In someembodiments, R¹ is phenyl substituted with 1 R⁹ in the ortho position.In some embodiments, R¹ is phenyl substituted with 1 R⁹ in the metaposition. In some embodiments, R⁹ is haloalkoxy (e.g., difluoromethoxyor trifluoromethoxy). In some embodiments, R⁹ is —CN. In someembodiments, R⁹ is —C(O)OR^(a). In some embodiments, R^(a) is hydrogen.In some embodiments, R⁹ is —C(Y)NR^(b)R^(b′). In some embodiments, Y isO. In some embodiments, R^(b) and R^(b′) are both hydrogen. In someembodiments, R¹ is:

In some embodiments, one of R^(b) and R^(b′) is hydrogen and the otheris C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R¹ is phenyl substituted with 2 R⁹. In someembodiments, each R⁹ is independently halo (e.g., each R⁹ is fluoro oreach R⁹ is chloro). In some embodiments, one R⁹ is fluoro and the otheris chloro. In some embodiments, one R⁹ is halo (e.g., chloro) and theother is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy).

In some embodiments, 2 R⁹ are taken together with the atoms to whichthey are attached to form a heterocyclyl ring, e.g., a 5-memberedheterocyclyl ring (e.g., a dioxole ring). In some embodiments, thedioxole ring is unsubstituted. In some embodiments, the dioxole ring issubstituted. In some embodiments, the dioxole ring is substituted withtwo fluoro substituents. In some embodiments, R¹ is selected from:

In some embodiments, R¹ is aralkyl (e.g., benzyl). In some embodiments,R¹ is aralkyl substituted with 2 R⁹ (e.g., benzyl substituted with 2R⁹). In some embodiments, 2 R⁹ substituents are on the phenyl ring. Insome embodiments, each R⁹ is independently halo (e.g., each R⁹ ischloro).

In some embodiments, R¹ is alkyl (e.g., methyl).

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, R² is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R² is C₁-C₈ alkyl substituted with 1 R¹¹ (e.g., methylsubstituted with 1 R¹¹). In some embodiments, R¹¹ is heterocyclyl (e.g.,morpholino).

In some embodiments, R² is aryl (e.g., phenyl). In some embodiments, R²is phenyl substituted with 1 R¹¹. In some embodiments, R¹¹ is —CN. Insome embodiments, R¹¹ is —OR^(d). In some embodiments, R^(d) is C₁-C₈alkyl (e.g., methyl). In some embodiments. R¹¹ is halo.

In some embodiments, R² is halo (e.g., fluoro, chloro, bromo or iodo).

In some embodiments, R² is —NR^(c)C(Y)R^(c′). In some embodiments, R^(c)is hydrogen. In some embodiments, Y is O. In some embodiments, R^(c′) isalkyl (e.g., methyl). In some embodiments, R^(c′) is aryl (e.g.,phenyl). In some embodiments, R^(c′) is phenyl substituted with 1 R⁸. Insome embodiments, R⁸ is —OR^(d). In some embodiments, R^(d) is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R^(c′) is heteroaryl. In some embodiments, R^(c′)is furanyl. In some embodiments, R^(c′) is pyridyl. In some embodiments,R^(c′) is pyridyl substituted with 1 R⁸. In some embodiments, R⁸ is—OR^(d). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R^(c′) is cyclyl (e.g., cyclohexyl). In someembodiments, R^(c′) is cyclohexyl substituted with 1 R⁸. In someembodiments, R⁸ is —OR^(d) in some embodiments, R^(d) is C₁-C₈ alkyl(e.g., methyl).

In some embodiments, R^(c′) is heterocyclyl (e.g., tetrahydropyranyl).

In some embodiments, R² is —NR^(b)R^(b′) in some embodiments, R^(b) andR^(b′) are both hydrogen. In some embodiments, R^(b) and R^(b′) are eachindependently C₁-C₈ alkyl (e.g., R^(b) and R^(b′) are both methyl).

In some embodiments, R¹ is —OR^(d). In some embodiments, R^(d) is C₁-C₈alkyl (e.g., methyl or ethyl). In some embodiments, R^(d) is ethylsubstituted with 1 R⁸. In some embodiments, R⁸ is —OR^(d). In someembodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl). In some embodiments,R¹ is —OCH₂CH₂OCH₃. In some embodiments, R² is —OCH₂CH₂OCH₂CH₂CH₃. Insome embodiments, R² is —OCH₂CH₂OCH₂CH₂CH₂OCH₃.

In some embodiments, n is 2.

In some embodiments, one R¹ is C₁-C₈ alkyl (e.g., methyl) and the otheris halo (e.g., chloro).

In some embodiments, one R² is —OR^(d) and the other is halo (e.g.,chloro). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, X¹ and X⁴ are N and X², X³ and X⁵ are CH.

In some embodiments, X¹ and X³ are N and X², X⁴ and X⁵ are CH.

In some embodiments, X² and X³ are N and X¹, X⁴ and X⁵ are CH.

In some embodiments, X² and X⁴ are N and X¹, X³ and X⁵ are CH.

In some embodiments, the compound is:

wherein s is 0, 1, 2, 3 or 4.

In some embodiments, R⁹ is —C(O)NH₂, C₁-C₄ alkoxy, or substituted C₁-C₄alkoxy. In some embodiments, R⁹ is halo,

In some embodiments, the compound is:

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, R₁ is heteroaralkyl (e.g.,—CH₂-pyridyl). In some embodiments, LR¹ is NH(CH₃).

In some embodiments, the compound is:

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, R₁ is heteroaralkyl (e.g.,—CH₂-pyridyl). In some embodiments, LR¹ is NH(CH₃).

In some embodiments, the compound is:

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, R₁ is heteroaralkyl (e.g.,—CH₂-pyridyl). In some embodiments, LR¹ is NH(CH₃).

In some embodiments, the compound is:

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, R₁ is heteroaralkyl (e.g.,—CH₂-pyridyl). In some embodiments, LR¹ is NH(CH₃).

In some embodiments, the compound is:

wherein t is 1-3.

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments. R¹ is heteroaralkyl (e.g.,—CH₂-pyridyl). In some embodiments, LR¹ is NH(CH₃). In some embodiments,R¹ is independently halo, nitrile, C₁-C₄ alkoxy, —C(O)NH₂, hydroxy, orC₁-C₄ hydroxyalkyl. In some embodiments, R¹¹ is fluoro. In someembodiments, R¹¹ is methoxy, ethoxy, or methoxyethoxy ether. In someembodiments, R¹¹ is —OCH₂CH₂OCH₃. In some embodiments, R¹¹ is—OCH₂CH₂OCH₂CH₂CH₃. In some embodiments, R¹¹ is —OCH₂CH₂OCH₂CH₂OCH₃.

In some embodiments, the compound is:

wherein t is 1-3.

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, LR¹ is NH(CH₃). In some embodiments,R¹¹ is independently halo, nitrile, C₁-C₄ alkoxy, —C(O)NH₂, hydroxy, orC₁-C₄ hydroxyalkyl. In some embodiments, R¹¹ is fluoro. In someembodiments, R¹¹ is methoxy, ethoxy, or methoxyethoxy ether. In someembodiments, R¹¹ is —OCH₂CH₂OCH₃. In some embodiments, R¹¹ is—OCH₂CH₂OCH₂CH₂CH₃. In some embodiments. R¹¹ is —OCH₂CH₂CH₂OCH₂CH₂OCH₃.

In some embodiments, the compound is:

wherein t is 1-3.

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, LR¹ is NH(CH₃). In some embodiments,R¹¹ is independently halo, nitrile, C₁-C₄ alkoxy, —C(O)NH₂, hydroxy, orC₁-C₄ hydroxyalkyl. In some embodiments, R¹¹ is fluoro. In someembodiments, R¹¹ is methoxy, ethoxy, or methoxyethoxy ether. In someembodiments, R¹¹ is —OCH₂CH₂OCH₃. In some embodiments, R¹¹ is—OCH₂CH₂OCH₂CH₂CH₃. In some embodiments, R¹¹ is —OCH₂CH₂OCH₂CH₂OCH₃.

In some embodiments, the compound is:

wherein t is 1-3.

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, LR¹ is NH(CH₃). In some embodiments,R¹¹ is independently halo, nitrile, C₁-C₄ alkoxy, —C(O)NH₂, hydroxy, orC₁-C₄ hydroxyalkyl. In some embodiments, R¹¹ is fluoro. In someembodiments, R¹¹ is methoxy, ethoxy, or methoxyethoxy ether. In someembodiments, R¹¹ is —OCH₂CH₂OCH₃. In some embodiments, R¹¹ is—OCH₂CH₂OCH₂CH₂CH₃. In some embodiments R¹¹ is —OCH₂CH₂OCH₂CH₂OCH₃.

Compounds of Formula (III)

The following aspects and embodiments relate to compounds of formula(III).

-   Item 15. The compound according to item 1 represented by general    formula (III) or a salt thereof,

wherein:

A is CH or N;

L is O, a direct bond or NH;

one of X¹, X², X³, X⁴ and X⁵ is N and the others are CH;

m is 1, 2 or 3;

n is 1, 2, 3 or 4;

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₅ alkynyl, alkoxyalkyl,hydroxyalkyl, heteroaryl, heteroarylalkyl, arylalkyl, —C(Y)R^(e),cyclyl, cyclylalkyl or heterocyclyl, each of which is optionallysubstituted with 1-3 R⁷;

R² is aryl or heteroaryl, each of which is optionally substituted with1-5 R⁹;

each R³ or R⁴ is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d′), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹⁰;

each R⁷, R⁹ and R¹⁰ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl,heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹²;wherein two R⁷ or two R⁹ are optionally be taken together with the atomsto which they are attached to form an optionally substituted cyclyl,heterocyclyl, aryl or heteroaryl ring;

R¹² is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹³;

R¹³ is independently C₁-C₈ alkyl, haloalkyl, halo, heterocyclyl, cyclyl,oxo or —C(Y)NR^(b)R^(b′);

Y is O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,acyl, cyclyl, heterocyclyl, aryl, haloalkyl, alkoxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cyclylalkyl,heterocyclylalkyl, arylalkyl or heteroarylalkyl.

-   Item 16. The compound according to item 15 represented by general    formula (III) or a salt thereof,

wherein:

m is 1;

n is 1;

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, heteroaryl,heterocyclyl, arylalkyl, cyclylalkyl, heteroarylalkyl, alkoxyalkyl,hydroxyalkyl or —C(O)R^(e), each of which is optionally substituted with1-3 R⁷;

R² is aryl, heteroaryl or benzofuryl, each of which is optionallysubstituted with 1-5 R⁹;

each R³ or R⁴ is independently hydrogen, C₁-C₈ alkyl, halo, haloalkyl or—OR^(d);

R⁶ is hydrogen or C₁-C₈ alkyl;

each R⁷ and R⁹ is independently C₁-C₈ alkyl, aryl, heteroaryl, halo,haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO₂,—C(O)OR^(a), —C(O)NR^(b)R^(b′), —NR^(b)R^(b′), —OR^(d), —C(O)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹²;

R¹² is independently C₁-C₈ alkyl, oxo, halo, haloalkyl, —CN,—C(O)NR^(b)R^(b′) or —C(O)R^(e) each of which is optionally substitutedwith 1-3 R¹³;

R¹³ is independently C₁-C₈ alkyl, halo or heterocyclyl; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₃ alkyl, cyclyl, heterocyclyl, arylalkyl,alkoxyalkyl, heterocyclylalkyl, heteroarylalkyl, alkylaminoalkyl,dialkylaminoalkyl or phenyl.

-   Item 17. The compound according to Item 16 represented by general    formula (III) or a salt thereof,

wherein:

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₄ alkenyl, C₂-C₈ alkynyl, alkoxyalkyl,hydroxyalkyl, imidazolyl, pyridylalkyl, phenylalkyl, oxazolylalkyl,thienylalkyl, thiazolidinyl isoindolyl, —C(O)R^(e), dihydroindenyl,C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, piperidyl, morpholinyl,pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionallysubstituted with 1-3 R⁷;

R² is phenyl, naphthyl, benzofuryl, indazolyl, benzothienyl, pyridyl,pyrimidinyl, dihydrobenzodioxinyl, benzodioxolyl, benzoimidazolyl,isoxazolyl, pyrazolyl, indolinyl or benzoisoxazolyl, each of which isoptionally substituted with 1-5 R⁹;

each R³ or R⁴ is independently hydrogen, C₁-C₅ alkyl, halo, haloalkyl or—OR^(d);

R⁶ is hydrogen or C₁-C₈ alkyl;

each R⁷ and R⁹ is independently C₁-C₈ alkyl, phenyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO₂, —C(O)OR^(a),—C(O)NR^(b)R^(b′), —NR^(b)R^(b′), —OR^(d), —C(O)R^(e) or —S(O)_(q)R^(f);and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl,alkoxyalkyl, morholinylalkyl, oxazolidinylalkyl, imidazolylalkyl,tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl,thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl,dihydrobenzoxazinylalkyl, tetrahydrofurylalkyl, tetrahydrofuryl,alkylaminoalkyl, dialkylaminoalkyl or phenyl.

-   Item 18. The compound according to item 16 represented by general    formula (III) or a salt thereof,

wherein:

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, alkoxyalkyl,hydroxyalkyl, imidazolyl, furylalkyl, pyridylalkyl, phenylalkyl,oxazolylalkyl, thienylalkyl, thiazolidinyl, isoindolyl, —C(O)R^(e),dihydroindenyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, piperidyl,morpholinyl, pyrrolidinyl, azetidinyl or piperazinyl, each of which isoptionally substituted with 1-3 R⁷;

R² is phenyl, naphthyl, benzofuryl, indazolyl, benzothienyl, pyridyl,pyrimidinyl, dihydrobenzodioxinyl, benzodioxolyl, benzoimidazolyl,isoxazolyl, pyrazolyl, indolinyl or benzisoxazolyl, each of which isoptionally substituted with 1-5 R⁹;

each R³ or R⁴ is independently hydrogen, C₁-C₈ alkyl, halo, haloalkyl or—OR^(d);

R⁶ is hydrogen or C₁-C₈ alkyl;

each R⁷ and R⁹ is independently C₁-C₈ alkyl, phenyl, halo, haloalkyl,haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO₂, —C(O)OR^(a),—C(O)NR^(b)R^(b′), —NR^(b)R^(b′), —OR^(d), —C(O)R^(e) or —S(O)_(q)R^(f),each of which is optionally substituted with 1-3 R¹²;

R¹² is independently C₁-C₈ alkyl, oxo, halo, haloalkyl, —CN,—C(O)NR^(b)R^(b′) or —C(O)R^(e), each of which is optionally substitutedwith 1-3 R¹³;

R¹³ is independently C₃-C₈ alkyl, halo or pyrrolidinyl; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, pyrrolidinyl,piperidyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl,alkoxyalkyl, morpholinylalkyl, oxazolidinylalkyl, imidazolylalkyl,tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl,thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl,dihydrobenzoxazinylalkyl, tetrahydrofurylalkyl, tetrahydrofuryl,alkylaminoalkyl, dialkylaminoalkyl or phenyl.

-   Item 19. The compound according to item 18 represented by general    formula (III) or a salt thereof,

wherein:

A is N;

R³ is hydrogen, C₁-C₈ alkyl, halo, haloalkyl, or —OR^(d);

R⁴ is hydrogen, C₁-C₈ alkyl, halo, or —OR^(d);

R⁷ is C₁-C₈ alkyl, phenyl, halo, haloalkyl, oxo, —C(O)OR^(a),—C(O)NR^(b)R^(b′) or —OR^(d) each of which is optionally substitutedwith 1-3 R¹²;

R⁹ is C₁-C₈ alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,alkoxyalkyl, —CN, —NO₂, —C(O)NR^(b)R^(b′), —C(O)OR^(a), —NR^(b)R^(b′),—OR^(d), —C(O)R^(e) or —S(O)_(q)R^(f), each of which is optionallysubstituted with 1-3 R¹²; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, pyrrolidinyl,piperidyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl,alkoxyalkyl, morpholinylalkyl, oxazolidinylalkyl, imidazolylalkyl,tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl,thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl,tetrahydrofurylalkyl, dihydrobenzoxazinylalkyl, tetrahydrofuryl,alkylaminoalkyl, dialkylaminoalkyl or phenyl.

-   Item 20. The compound according to item 17 or 19 represented by    general formula (III) or a salt thereof,

wherein:

A is N;

R³ is hydrogen, C₁-C₈ alkyl, halo, haloalkyl, or —OR^(d);

R⁴ is hydrogen, C₁-C₈ alkyl, halo, or —OR^(d);

R⁷ is C₁-C₈ alkyl, phenyl, halo, haloalkyl, oxo, —C(O)OR^(a),—C(O)NR^(b)R^(b′) or —OR^(d);

R⁹ is C₁-C₈ alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,alkoxyalkyl, —CN, —NO₂—C(O)NR^(b)R^(b′), —C(O)OR^(a), —NR^(b)R^(b′),—OR^(d), —C(O)R^(e) or —S(O)_(q)R^(f); and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, pyrrolidinyl,piperidyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl,alkoxyalkyl, morpholinylalkyl, oxazolidinylalkyl, imidazolylalkyl,tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl,thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl,tetrahydrofurylalkyl, tetrahydrofuryl, dihydrobenzoxazinylalkyl,alkylaminoalkyl, dialkylaminoalkyl or phenyl.

-   Item 21. The compound according to item 20 represented by general    formula (III) or a salt thereof,

wherein:

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, alkoxyalkyl,hydroxyalkyl, imidazolyl, furylalkyl, pyridylalkyl, phenylalkyl,oxazolylalkyl, thienylalkyl, isoindolyl, —C(O)R^(c), dihydroindenyl,C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, piperidyl, morpholinyl,pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionallysubstituted with 1-3 R⁷;

R² is phenyl, which is optionally substituted with 1-5 R⁹; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently hydrogen, C₁-C₈ alkyl, pyrrolidinyl, morpholinyl,tetrahydropyranyl, alkoxyalkyl, morpholinylalkyl,tetrahydropyranylalkyl, pyridylalkyl, thiazolylalkyl, pyrrolylalkyl,tetrahydrofuryl, alkylaminoalkyl or phenyl.

In some embodiments, R¹ is C₁-C₈ alkyl, which is optionally substitutedwith 1-3 R⁷; or when L is NR⁶, R¹ and R⁶ may be taken together with theatoms to which they are attached to form a heterocyclyl or heteroarylring that is optionally substituted with 1-3 R⁸.

In some embodiments, A is CH. In some embodiments, A is N.

In some embodiments, L is NR⁶. In some embodiments, R⁶ is hydrogen.

In some embodiments, R¹ is C₁-C₈ alkyl, e.g., methyl, ethyl, C₃ alkyl(e.g., n-propyl or isopropyl), C₄ alkyl (e.g., n-butyl, isobutyl ortert-butyl), or C₅ alkyl (e.g., pentan-3-yl).

In some embodiments, R¹ is C₁-C₈ alkyl substituted with 1-3 R⁷ (e.g.,C₁-C₈ alkyl substituted with 1 R⁷). In some embodiments, R¹ is methylsubstituted with 1 R⁷. In some embodiments, R¹ is cyclyl (e.g.,cyclopropyl). In some embodiments, R⁷ is aryl (e.g., phenyl).

In some embodiments, R¹ is ethyl substituted with 1 R⁷. In someembodiments, R⁷ is aryl (e.g., phenyl). In some embodiments, R⁷ is—OR^(d). In some embodiments, R^(d) is aryl (e.g., phenyl).

In some embodiments, R¹ is n-propyl substituted with 1 R⁷. In someembodiments, R¹ is —OR^(d). In some embodiments, R^(d) is C₁-C₈ alkyl(e.g., C₃ alkyl, e.g., n-propyl).

In some embodiments, R¹ is C₁-C₈ alkyl substituted with 3 R⁷. In someembodiments, R¹ is ethyl substituted with 3 R⁷. In some embodiments,each R⁷ is independently halo (e.g., each R⁷ is fluoro). In someembodiments, R¹ is 2,2,2-trifluoroethyl.

In some embodiments, R¹ is C₂-C₈ alkenyl, e.g., C₃ alkenyl (e.g.,—CH₂—CH═CH₂).

In some embodiments, R¹ is C₂-C₈ alkynyl, e.g., C₃ alkynyl (e.g.—CH₂—C≡CH).

In some embodiments, R¹ is cyclyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl). In some embodiments, the cyclyl group is abicyclic group (e.g., indanyl).

In some embodiments, R¹ is heterocyclyl (e.g., piperidyl). In someembodiments, R¹ is piperidyl substituted with 1 R⁷. In some embodiments,R¹ is —C(Y)R^(e). In some embodiments, Y is O. In some embodiments,R^(e) is C₁-C₈ alkyl (e.g., methyl). In some embodiments, R¹ is —OR^(d).

In some embodiments, R⁶ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R¹ and R⁶ are taken together with the atoms towhich they are attached to form a heterocyclyl ring (e.g. a pyrrolidinering).

In some embodiments, R¹ and R⁶ are taken together with the atoms towhich they are attached to form a heteroaryl ring (e.g., an imidazolering).

In some embodiments, L is O.

In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R² is aryl (e.g., phenyl). In some embodiments, R²is unsubstituted phenyl. In some embodiments, R² is phenyl substitutedwith 1-3 R⁹. In some embodiments, R¹ is phenyl substituted with 1 R⁹.

In some embodiments, R² is:

In some embodiments, R⁹ is halo (e.g., fluoro or chloro). In someembodiments, R⁹ is —CN. In some embodiments, R⁹ is —NO₂. In someembodiments, R⁹ is haloalkoxy (e.g., trifluoroethoxy). In someembodiments, R⁹ is —NR^(b)R^(b′). In some embodiments, R^(b) and R^(b′)are each independently C₁-C₈ alkyl (e.g., R^(b) and R^(b′) are bothmethyl).

In some embodiments, R⁹ is —OR^(d). In some embodiments, R⁹ is—OCH₂CH₂OCH₃. In some embodiments, R⁹ is —OCH₂CH₂OCH₂CH₂CH₃. In someembodiments, R⁹ is —OCH₂CH₂OCH₂CH₂OCH₃. In some embodiments, R^(d) ishydrogen. In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl). Insome embodiments, R^(d) is ethyl.

In some embodiments, R⁹ is hydroxyalkyl (e.g., —CH₂OH). In someembodiments, R⁹ is alkoxyalkyl (e.g., —CH—O—CH₃). In some embodiments,R⁹ is —C(O)R^(e). In some embodiments, R^(e) is heterocyclyl (e.g.,morpholino). In some embodiments, R⁹ is —S(O)_(q)R^(f). In someembodiments, q is 1. In some embodiments, R^(f) is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, R² is phenyl substituted with 2 R⁹. In someembodiments, each R⁹ is independently halo (e.g., each R⁹ is fluoro). Insome embodiments, each R⁹ is independently —OR^(d). In some embodiments,each R^(d) is independently C₁-C₈ alkyl (e.g., each R^(d) is methyl).

In some embodiments, R² is heteroaryl. In some embodiments, R² is a6-membered heteroaryl. In some embodiments, R² is a 6-memberednitrogen-containing heteroaryl, e.g., pyridyl. In some embodiments, R²is unsubstituted pyridyl.

In some embodiments, R² is pyridyl substituted with 1 R⁹. In someembodiments, R⁹ is —OR^(d). In some embodiments, R^(d) is C₁-C₈ alkyl(e.g., methyl).

In some embodiments, R² is a 5-membered heteroaryl. In some embodiments,R² is a 5-membered nitrogen-containing heteroaryl (e.g., pyrrolyl oroxazolyl).

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, R⁴ is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R⁴ is —OR^(d). In some embodiments, R^(d) is C₁-C₈ alkyl(e.g., methyl). In some embodiments, R⁴ is halo. In some embodiments, R⁴is methoxy. In some embodiments, R^(d) is C₁-C₈ alkyl.

In some embodiments, the compound has the following structure:

wherein one of X¹ and X² is N and the other is CH.

In some embodiments, X¹ is CH and X² is N. In some embodiments, X¹ is Nand X² is CH. In some embodiments, the compound has the followingstructure:

In some embodiments, R² is aryl. In some embodiments, R² is heteroaryl.In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, the compound has the following structure:

In some embodiments, R² is aryl. In some embodiments, R² is heteroaryl.In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, the compound has the following structure:

In some embodiments, R² is aryl. In some embodiments, R² is heteroaryl.In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, the compound has the following structure:

wherein R¹ is C₁-C₈ alkyl, which is optionally substituted with 1-3 R⁷.

In some embodiments, R² is aryl. In some embodiments, R² is heteroaryl.In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, the compound has the following structure:

In some embodiments, R² is aryl. In some embodiments, R² is heteroaryl.In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R² is

In some embodiments, the compound has the following structure:

In some embodiments, R² is aryl. In some embodiments, R² is heteroaryl.In some embodiments R¹ is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R² is

In some embodiments, the compound has the following structure:

wherein p is 1, 2, 3, 4 or 5.

In some embodiments, L is NR⁶. In some embodiments, L is O. In someembodiments, R¹ is hydrogen or C₁-C₈ alkyl. In some embodiments, R¹ iscyclyl or heterocyclyl. In some embodiments, R¹ is aralkyl orheteroaralkyl. In some embodiments, R¹ is methyl, cyclohexyl, t-butyl,or

In some embodiments, R⁶ is hydrogen or C₁-C₈ alkyl.In some embodiments, R⁹ is C₁-C₈ alkyl, halo, —CN, or —OR^(d). In someembodiments, R³ is hydrogen.

In some embodiments, the compound has the following structure:

wherein p is 1, 2, 3, 4 or 5.

In some embodiments, L is NR⁶. In some embodiments, L is O. In someembodiments, R¹ is hydrogen or C₁-C₈ alkyl. In some embodiments, R¹ iscyclyl or heterocyclyl. In some embodiments, R¹ is aralkyl orheteroaralkyl. In some embodiments, R¹ is methyl, cyclohexyl, t-butyl,or

In some embodiments, R¹ is hydrogen or C₁-C₈ alkyl. In some embodiments,R⁹ is C₁-C₈ alkyl, halo, —CN, or —OR^(d). In some embodiments, R³ ishydrogen.Compounds of Formula (IV)

The following aspects and embodiments relate to compounds of formula(IV), corresponding to formula (I) of U.S. Provisional PatentApplication No. 61/291,544, entitled “Therapeutic Compounds and RelatedMethods of Use” filed on Dec. 31, 2009, and incorporated herein byreference in its entirety.

-   Item 38. A compound of formula (IV):

wherein:

A is CH, CR⁴ or N;

B is aryl or a 5- or 6-membered heteroaryl;

m is 0, 1, 2, 3, 4 or 5;

E is aryl or a 5-membered heteroaryl;

when E is aryl, n is 1, 2, 3 or 4; and when E is a 5-memberedheteroaryl, n is 0, 1, 2 or 3:

L is NR⁵ or O;

one of X and Z is N and the other is CH;

p is 0, 1, 2, 3 or 4;

each R¹, R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or —S(O)_(q)R^(f),each of which may be optionally substituted with 1-3 R⁶; wherein two R¹,together with the atoms to which they are attached, may form anoptionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;

R⁴ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl,heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;

R⁵ is hydrogen; or when in is not 0, R⁵ and 1 R¹ may be taken togetherwith the atoms to which they are attached to form an optionallysubstituted heteroaryl or heterocyclyl ring;

each R⁶ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d)—SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f), each of which may be optionally substituted with 1-3R⁷;

each R⁷ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(v′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f);

each Y is independently O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, acyl, aryl, heteroaryl, cyclyl, heterocyclyl,aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy andsilylalkoxyalkyl, each of which may be optionally substituted with 1-3R⁶, wherein R^(b) and R^(b′), together with the atoms to which they areattached, may form an optionally substituted cyclyl or heterocyclylring;

or a pharmaceutically acceptable derivative or prodrug thereof,

wherein when B is phenyl, two R¹ are not taken together to form apyrazole ring; when B is phenyl, R² is not

and where in the compound is not:

In some embodiments, when B is phenyl, R² is not a substituted pyridyl.In some embodiments, when B is phenyl and n=1, R² is not a substitutedpyridyl.

In some embodiments, when X is N, B is not 4-pyridyl.

In some embodiments, each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d),R^(d′), R^(e), R^(e′) and R^(f) is independently selected from hydrogen,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, acyl, aryl, heteroaryl,cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl,heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy and silylalkoxyalkyl, each of which may beoptionally substituted with 1-3 R⁶.

In some embodiments, B is aryl.

-   Item 39. A compound of formula (IV):

wherein:

A is CH, CR⁴ or N;

B is aryl or a 5-membered heteroaryl;

m is 0, 1, 2, 3, 4 or 5;

E is aryl or a 5-membered heteroaryl;

when E is aryl, n is 1, 2, 3 or 4; and when E is a 5-memberedheteroaryl, n is 0, 1, 2 or 3;

L is NR⁵ or O;

one of X and Z is N and the other is CH;

p is 0, 1, 2, 3 or 4;

each R¹, R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR,—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;wherein two R¹, together with the atoms to which they are attached, mayform an optionally substituted cyclyl, heterocyclyl, aryl or heteroarylring;

R⁴ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl,heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;

R⁵ is hydrogen; or when m is not 0, R⁵ and 1 R¹ may be taken togetherwith the atoms to which they are attached to form an optionallysubstituted heteroaryl or heterocyclyl ring:

each R⁶ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f), each of which may be optionally substituted with 1-3R⁷;

each R⁷ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, aralkyl, heteroalkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d) SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f);

each Y is independently O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, acyl, aryl, heteroaryl, cyclyl, heterocyclyl,aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy andsilylalkoxyalkyl, each of which may be optionally substituted with 1-3R⁶ wherein R^(b) and R^(b′), together with the atoms to which they areattached, may form an optionally substituted cyclyl or heterocyclylring;

or a pharmaceutically acceptable derivative or prodrug thereof,

wherein when B is phenyl, two R¹ are not taken together to form apyrazole ring; and

when B is phenyl, R² is not

In some embodiments, each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d),R^(d′), R^(e), R^(e′) and R^(f) is independently selected from hydrogen,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, acyl, aryl, heteroaryl,cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl,heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy and silylalkoxyalkyl, each of which may beoptionally substituted with 1-3 R⁶.

In some embodiments, when B is phenyl, R¹ is not a substituted pyridyl.In some embodiments, when B is phenyl and n=1, R² is not a substitutedpyridyl.

In one aspect, the invention features a compound of formula (IV):

wherein:

A is CH, CR⁴ or N;

B is aryl or a 5-membered heteroaryl;

E is aryl or a 5-membered heteroaryl;

L is NR⁵ or O;

one of X and Z is N and the other is CH;

m is 0, 1, 2, 3, 4 or 5;

n is 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

each R¹ and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;wherein two R¹, together with the atoms to which they are attached, mayform an optionally substituted cyclyl, heterocyclyl, aryl or heteroarylring;

each R² is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl,heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;wherein two R¹, together with the carbons to which they are attached,may form an optionally substituted cyclyl, heterocyclyl, aryl orheteroaryl ring;

R⁴ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl,heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;

R⁵ is hydrogen; or when m is not 0, R⁵ and 1 R¹ may be taken togetherwith the atoms to which they are attached to form an optionallysubstituted heteroaryl or heterocyclyl ring;

each R⁶ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′, —SO) ₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f), each of which may be optionally substituted with 1-3R⁷;

each R⁷ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f);

Y is O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl,cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of whichmay be optionally further substituted with 1-3 R⁶ wherein R^(b) andR^(b′), together with the atoms to which they are attached, may form anoptionally substituted cyclyl or heterocyclyl ring;

or a pharmaceutically acceptable derivative or prodrug thereof,

wherein when B is phenyl, two R¹ are not taken together to form apyrazole ring.

In some embodiments, each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d),R^(d′), R^(e), R^(e′) and R^(f) is independently selected from hydrogen,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, acyl, aryl, heteroaryl,cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl,heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy and silylalkoxyalkyl, each of which may beoptionally substituted with 1-3 R⁶.

In one aspect, the invention features a compound of formula (IV):

wherein:

A is CH, CR⁴ or N;

B is aryl or a 5-membered heteroaryl;

E is aryl or a 5-membered heteroaryl;

L is NR⁵ or O:

one of X and Z is N and the other is CH;

m is 0, 1, 2, 3, 4 or 5;

n is 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

each R¹ and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;wherein two R¹, together with the atoms to which they are attached, mayform an optionally substituted cyclyl, heterocyclyl, or aryl ring;

each R² is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl,heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;wherein two R¹, together with the carbons to which they are attached,may form an optionally substituted cyclyl, heterocyclyl, aryl orheteroaryl ring;

R⁴ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl,heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally substituted with 1-3 R⁶;

R⁵ is hydrogen; or when m is not 0, R⁵ and 1 R¹ may be taken togetherwith the atoms to which they are attached to form an optionallysubstituted heteroaryl or heterocyclyl ring;

each R⁶ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR, —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f), each of which may be optionally substituted with 1-3R⁷;

each R⁷ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN,—NO₂—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR³C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f);

Y is O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e), R^(e′)and R^(f) is independently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl,cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of whichmay be optionally further substituted with 1-3 R⁶, wherein R^(b) andR^(b′), together with the atoms to which they are attached, may form anoptionally substituted cyclyl or heterocyclyl ring;

In some embodiments, A is N. In some embodiments, A is CH. In someembodiments, A is CR⁴.

In some embodiments, B is aryl (e.g., phenyl).

In some embodiments, m is 0.

In some embodiments, m is 1. In some embodiments, m is 2. In someembodiments, m is 3.

In some embodiments, R¹ is in the ortho position. In some embodiments,R¹ is in the meta position. In some embodiments, R¹ is in the paraposition.

In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl or tert-butyl). Insome embodiments, R¹ is heteroaryl (e.g., oxazolyl, oxadiazolyl orquinazolinyl).

In some embodiments, R¹ is heteroaryl substituted with 1-3 R⁶ (e.g., 1R⁶).

In some embodiments, R¹ is oxadiazolyl substituted with 1 R⁶. someembodiments, R⁶ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R¹ is heteroaryl substituted with 2 R⁶. In someembodiments, R¹ is quinazolinyl substituted with 2 R⁶. In someembodiments, one R⁶ is halo (e.g., bromo) and the other is heteroaryl(e.g., pyridyl).

In some embodiments, m is 1 and R¹ is halo (e.g., fluoro, chloro orbromo). In some embodiments, m is 2 and each R¹ is halo (e.g., fluoro,chloro or bromo). In some embodiments, m is 3 and each R¹ is halo (e.g.,fluoro, chloro or bromo). In some embodiments, R¹ is haloalkyl (e.g.,trifluoromethyl). In some embodiments, R¹ is haloalkoxy (e.g.,difluoromethoxy or trifluoromethoxy).

In some embodiments, R¹ is haloalkoxy substituted with 1 R⁶. In someembodiments, R¹ is —O—CF₂—R⁶. In some embodiments, R⁶ is—C(Y)NR^(b)R^(b′). In some embodiments, Y is O, R^(b) is hydrogen andR^(b′) is C₁-C₈ alkyl (e.g., methyl). In some embodiments, R¹ is—O—CF₂—CH₂—R⁶. In some embodiments, R⁶ is —OR^(d). In some embodiments,R^(d) is hydrogen. In some embodiments, R^(d) is C₁-C₈ alkyl (e.g.,methyl). In some embodiments, R⁶ is —NR^(b)R^(b′). In some embodiments,R^(b) and R^(b′) are each independently C₁-C₈ alkyl (e.g., R^(b) andR^(b′) are both methyl). In some embodiments, R⁶ is heterocyclyl (e.g.,morpholino).

In some embodiments, R¹ is aminoalkyl. In some embodiments, R¹ is—CH₂NH₂. In some embodiments, R¹ is alkylaminoalkyl. In someembodiments, R¹ is —CH₂NHCH₂CH₂CH₃. In some embodiments, R¹ isdialkylaminoalkyl. In some embodiments, R¹ is —CH₂N(CH(CH₃)₂)₂.

In some embodiments, R¹ is hydroxyalkyl. In some embodiments, R¹ is—CH₂OH.

In some embodiments, R¹ is —CN.

In some embodiments, R¹ is —NO.

In some embodiments, R¹ is —C(O)OR^(a). In some embodiments, R^(a) ishydrogen. In some embodiments, R^(a) is C₁-C₈ alkyl (e.g., methyl orethyl).

In some embodiments, R¹ is —NR^(c)C(Y)R^(c′). In some embodiments, oneof R^(c) and R^(c′) is hydrogen and the other is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, R¹ is —OR^(d). In some embodiments, R^(d) ishydrogen. In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl orethyl).

In some embodiments, R¹ is —SO₂NR^(b)R^(b′). In some embodiments, R^(b)and R^(b′) are both hydrogen.

In some embodiments, R¹ is —C(Y)R^(e). In some embodiments, Y is O. Insome embodiments, R^(e) is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R^(e) is heterocyclyl (e.g., pyrrolidinyl, piperidinyl ormorpholino).

In some embodiments, R¹ is —C(Y)NR^(b)R^(b′). In some embodiments, Y isS. In some embodiments, Y is O. In some embodiments, R^(b) and R^(b′)are both hydrogen. In some embodiments, R^(b) is hydrogen. In someembodiments, R^(b) is hydrogen and R^(b′) is aralkyl. In someembodiments, R^(b) is hydrogen and R^(b′) is optionally substitutedbenzyl. In some embodiments, R^(b′) is C₁-C₈ alkyl, e.g., methyl, ethyl,C₃ alkyl (e.g., n-propyl or isopropyl), C₄ alkyl (e.g., n-butyl,sec-butyl or tert-butyl), C₅ alkyl (e.g., n-pentyl, isopentyl orpentan-3-yl), C₆ alkyl (e.g., n-hexyl or 3,3-dimethylbutan-2-yl), or C₇alkyl (e.g., n-heptyl or 2-heptyl).

In some embodiments, R^(b′) is C₁-C₈ alkyl substituted with 1 R⁶. Insome embodiments, R⁶ is —OR^(d). In some embodiments, R^(d) is aryl(e.g., phenyl). In some embodiments, R^(b′) is C₂-C₈ alkenyl, e.g., C₃alkenyl (e.g., —CH₂—CH═CH₂). In some embodiments, R^(b′) is C₂-C₈alkynyl, e.g., C₃ alkenyl (e.g., —CH₂—C≡CH).

In some embodiments, R^(b′) is aryl (e.g., phenyl). In some embodiments,R^(b′) is aryl substituted with 1 R⁶ (e.g., phenyl substituted with 1R⁶). In some embodiments, R⁶ is haloalkyl (e.g., trifluoromethyl). Insome embodiments, R^(b′) is cyclyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl). In some embodiments, R^(b′) iscyclyl substituted with 1 R⁶ (e.g., cyclopropyl substituted with 1 R⁶ orcyclopentyl substituted with 1 R⁶). In some embodiments, R⁶ is C₁-C₈alkyl (e.g., methyl). In some embodiments, R⁶ is —OR^(d). In someembodiments, R^(d) is aralkyl (e.g., benzyl).

In some embodiments, R^(b′) is cyclohexyl substituted with 1 R⁶. In someembodiments, R⁶ is —C(O)OR^(a). In some embodiments, R^(a) is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R^(b′) is bicyclyl (e.g., indanyl). In someembodiments, R^(b′) is heterocyclyl, e.g., a 6-membered heterocyclyl. Insome embodiments, R^(b′) is a 6-membered oxygen-containing heterocyclyl(e.g., tetrahydropyranyl). In some embodiments, R^(b′) is a 6-memberednitrogen-containing heterocyclyl (e.g., piperidinyl).

In some embodiments, R^(b) is heterocyclyl substituted with 1 R⁶ (e.g.,piperidinyl substituted with 1 R⁶). In some embodiments, R⁶ is—C(O)OR^(a). In some embodiments, R^(a) is C₁-C₈ alkyl (e.g., ethyl). Insome embodiments, R⁶ is —C(Y)R^(e). In some embodiments, Y is O. In someembodiments, R^(e) is C₁-C₈ alkyl (e.g., methyl or ethyl).

In some embodiments, R^(b′) is aralkyl. In some embodiments, the alkylis a C₁-C₈ alkyl (e.g., C₁, C₂, C₃ or C₄ alkyl). In some embodiments,the alkyl is a straight-chain alkyl. In some embodiments, the alkyl is abranched alkyl. In some embodiments, the aryl is phenyl. In someembodiments, R^(b′) is benzyl. In some embodiments, R^(b′) isphenylethyl. In some embodiments, the aryl is substituted with 1 R⁶. Insome embodiments, R⁶ is C₁-C₈ alkyl (e.g., methyl). In some embodiments,R⁶ is halo (e.g., fluoro or chloro). In some embodiments, R⁶ ishaloalkyl (e.g., trifluoromethyl). In some embodiments, R⁶ is —OR^(d).In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl). In someembodiments, the aryl is substituted with 2 R⁶. In some embodiments,each R⁶ is independently —OR^(d). In some embodiments, each R^(d) isindependently C₁-C₈ alkyl (e.g., each R^(d) is methyl). In someembodiments, each R⁶ is independently halo (e.g., each R⁶ is fluoro).

In some embodiments, R^(b′) is heteroaralkyl. In some embodiments, thealkyl is a C₁-C₈ alkyl (e.g., C₁, C₂ or C₃ alkyl). In some embodiments,the alkyl is a straight-chain alkyl. In some embodiments, the alkyl is abranched alkyl. In some embodiments, the heteroaryl is pyridyl. In someembodiments, the heteroaryl is furanyl. In some embodiments, theheteroaryl is thiazolyl. In some embodiments, the heteroaryl is thienyl.In some embodiments, the heteroaryl is substituted with 1 R⁶. In someembodiments, R⁶ is C₁-C₈ alkyl (e.g., methyl). In some embodiments, R⁶is haloalkyl (e.g., trifluoromethyl).

In some embodiments, R^(b′) is cyclylalkyl. In some embodiments, thealkyl is a C₁-C₈ alkyl (e.g., C₁ alkyl). In some embodiments, the cyclylgroup is cyclopropyl. In some embodiments, the cyclyl group iscyclopentyl. In some embodiments, the cyclyl group is a bicyclic group.In some embodiments, the bicyclic group is indanyl. In some embodiments,R^(b′) is cyclylalkyl substituted with 1 R⁶. In some embodiments, R⁶ isaryl (e.g., phenyl).

In some embodiments, R^(b′) is heterocyclylalkyl. In some embodiments,the alkyl is a C₁-C₈ alkyl (e.g., C₁ alkyl). In some embodiments, theheterocyclyl group is tetrahydropyranyl.

In some embodiments, R^(b′) is haloalkyl (e.g., fluoroethyl,difluoroethyl, trifluoroethyl or trifluoropropyl).

In some embodiments, R^(b′) is alkoxyalkyl. In some embodiments, thealkyl is a C₁-C₈ alkyl (e.g., C₁, C₂, C₃ or C₄ alkyl). In someembodiments, the alkyl is a straight-chain alkyl. In some embodiments,the alkyl is a branched alkyl. In some embodiments, the alkoxy ismethoxy.

In some embodiments, R^(b) and R^(b′) are each independently C₁-C₈ alkyl(e.g., R^(b) and R^(b′) are both methyl, both ethyl or both isopropyl).

In some embodiments, R¹ and R⁵, together with the atoms to which theyare attached, form a heteroaryl ring (e.g., a substituted heteroarylring). In some embodiments, R¹ and R⁵, together with the atoms to whichthey are attached, form a heterocyclyl ring (e.g., a substitutedheterocyclyl ring).

In some embodiments, R¹, R⁵, B and L are taken together to form abicyclic heteroaryl or heterocyclic ring.

In some embodiments, R¹, R⁵, B and L are taken together to form

In some embodiments, R⁶ is halo. In some embodiments, R⁶ is at the 6, 7,or 8 position.

In some embodiments, R¹, R⁵, B and L are taken together to form a groupselected from:

In some embodiments, R² is aryl.

In some embodiments, each R¹ is independently C₁-C₈ alkyl (e.g., each R¹is methyl). In some embodiments, each R¹ is independently halo (e.g.,each R¹ is fluoro or each R¹ is chloro). In some embodiments, one R¹ isfluoro and the other is chloro. In some embodiments, one R¹ is chloroand the other is bromo.

In some embodiments, each R¹ is independently —OR^(d). In someembodiments, each R^(d) is independently C₁-C₈ alkyl (e.g., each R^(d)is methyl).

In some embodiments, one R¹ is halo (e.g., chloro) and the other isC₃-C₈ alkyl (e.g., methyl). In some embodiments, one R¹ is halo (e.g.,fluoro) and the other is heterocyclylalkyl (e.g., —CH₂-heterocyclyl). Insome embodiments, the heterocyclyl is morpholino. In some embodiments,the heterocyclyl is pyrrolidinyl. In some embodiments, the heterocyclylis piperazinyl. In some embodiments, the piperazinyl is substituted with1 R⁶. In some embodiments, R⁶ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R¹ is halo (e.g., fluoro or chloro) and theother is haloalkyl (e.g., trifluoromethyl).

In some embodiments, one R¹ is halo (e.g., chloro) and the other ishaloalkoxy (e.g., difluoromethoxy or trifluoromethoxy).

In some embodiments, one R¹ is halo (e.g., chloro) and the other is—C(O)OR^(a). In some embodiments, R^(a) is hydrogen.

In some embodiments, one R¹ is halo (e.g., fluoro or chloro) and theother is —C(Y)NR^(b)R^(b′). In some embodiments, Y is O. In someembodiments, R^(b) and R^(b′) are both hydrogen. In some embodiments,one of R^(b) and R^(b′) is hydrogen and the other is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, one R¹ is halo (e.g., chloro) and the other is—NR^(c)C(Y)R^(c′). In some embodiments, Y is O. In some embodiments,R^(c) is hydrogen and R^(c′) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R¹ is halo (e.g., fluoro or chloro) and theother is —OR^(d). In some embodiments, R^(d) is hydrogen. In someembodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R¹ is halo (e.g., fluoro or chloro) and theother is —CN.

In some embodiments, one R¹ is halo (e.g., chloro) and the other is—NO₂.

In some embodiments, one R¹ is —C(O)OR^(a) and the other is —NO₂. Insome embodiments, R^(a) is hydrogen.

In some embodiments, one R¹ is —C(O)O(R¹ and the other is —OR^(d). Insome embodiments, each R^(a) and R^(d) is hydrogen.

In some embodiments, one R¹ is —C(Y)NR^(b)R^(b′) and the other ishaloalkyl (e.g., trifluoromethyl). In some embodiments, R^(b) and R^(b′)are both hydrogen.

In some embodiments, one R¹ is —C(Y)NR^(b)R^(b′) and the other ishaloalkoxy (e.g., trifluoromethoxy). In some embodiments, R^(b) andR^(b′) are both hydrogen.

In some embodiments, one R¹ is —C(Y)NR^(b)R^(b′) and the other is—S(O)_(q)R^(f). In some embodiments, R^(b) and R^(b′) are both hydrogen.In some embodiments, R^(f) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R¹ is —C(Y)NR^(b)R^(b′) and the other is —CN.In some embodiments, R^(b) and R^(b′) are both hydrogen.

In some embodiments, one R¹ is —OR^(d) and the other is C₁-C₈ alkyl(e.g., methyl). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, one R¹ is —OR^(d) and the other is haloalkyl (e.g.,trifluoromethyl). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, one R¹ is —OR^(d) and the other is —C(O)OR^(a). Insome embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R^(a) is hydrogen. In some embodiments, R^(a) is C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R¹ is —OR^(d) and the other is—NR^(c)C(O)R^(c′). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g.,methyl). In some embodiments, R^(c) is hydrogen and R^(c′) is C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R¹ is haloalkyl (e.g., trifluoromethyl) and theother is —CN.

In some embodiments, two R¹, together with the atoms to which they areattached, are taken together to form a cyclyl ring (e.g., a substitutedcyclyl ring). In some embodiments, two R¹, together with the atoms towhich they are attached, are taken together to form a heterocyclyl ring(e.g., a substituted heterocyclyl ring). In some embodiments, two R¹,together with the atoms to which they are attached, are taken togetherto form a heteroaryl ring (e.g., a substituted heteroaryl ring).

In some embodiments, two R¹ and ring B are taken together to form agroup selected from:

In some embodiments, R² is aryl.

In some embodiments, each R¹ is independently halo (e.g., all three R¹are fluoro or all three R¹ are chloro).

In some embodiments, two R^(j) are independently halo (e.g., both arechloro) and the other is C₁-C₈ alkyl (e.g., methyl). In someembodiments, two R¹ are independently halo (e.g., both are chloro) andthe other is heteroaryl (e.g., pyrrolyl). In some embodiments, two R¹are independently halo (e.g., both are fluoro) and the other is—C(Y)NR^(b)R^(b′) (e.g., —C(O)NH₂). In some embodiments, two R¹ areindependently C₁-C₈ alkyl (e.g., both are methyl) and the other is halo(e.g., chloro or bromo).

In some embodiments, one R¹ is C₁-C₈ alkyl (e.g., methyl), and two R¹,together with the atoms to which they are attached, are taken togetherto form a heterocyclyl ring.

In some embodiments, one R¹ is —OR^(d), and two R¹, together with theatoms to which they are attached, are taken together to form aheterocycyl ring. In some embodiments, R^(d) is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, three R¹ and ring B are taken together to form agroup selected from:

In some embodiments, B is a 6-membered heteroaryl.

In some embodiments, B is pyridyl. In some embodiments, B is 3-pyridyl.In some embodiments, m is 2. In some embodiments, two R¹, together withthe atoms to which they are attached, are taken together to form an arylring (e.g., a phenyl ring). In some embodiments, in is 3. In someembodiments, one R¹ is —OR^(d), and two R¹, together with the atoms towhich they are attached, are taken together to form an aryl ring (e.g.,a phenyl ring). In some embodiments, R^(d) is hydrogen.

In some embodiments, B is pyrazolyl. In some embodiments, m is 2. Insome embodiments, two R¹, together with the atoms to which they areattached, are taken together to form a cyclyl ring (e.g., a cyclohexylring),

In some embodiments, B is selected from:

In some embodiments, B is a 5-membered heteroaryl (e.g., pyrazolyl).

In some embodiments, m is 1.

In some embodiments, R¹ is aryl (e.g., phenyl).

In some embodiments, R¹ is phenyl substituted with 1 R⁶.

In some embodiments, R⁶ is halo (e.g., chloro). In some embodiments, R¹is selected from:

In some embodiments, in is 2.

In some embodiments, one R¹ is C₁-C₈ alkyl (e.g., methyl) and the otheris aryl (e.g., phenyl). In some embodiments, the aryl is phenylsubstituted with 1 R⁶. In some embodiments, R⁶ is halo (e.g., chloro).In some embodiments, R¹ is:

In some embodiments, B is thienyl. In some embodiments, B is selectedfrom:

In some embodiments, m is 1. In some embodiments, m is 2. In someembodiments m is 2 and two R¹, together with the atoms to which they areattached, form an optionally substituted cyclyl, heterocyclyl, aryl orheteroaryl ring

In some embodiments, R¹ is —C(O)OR_(a). In some embodiments, R^(a) isC₁-C₈ alkyl (e.g., ethyl).

In some embodiments, R¹ is —C(Y)NR^(b)R^(b′). In some embodiments, Y isO. In some embodiments, R^(b) and R^(b′) are both hydrogen.

In some embodiments, m is 2.

In some embodiments, one R¹ is C₁-C₈ alkyl (e.g., methyl) and the otheris —C(Y)NR^(b)R^(b′). In some embodiments, Y is O. In some embodiments,R^(b) and R^(b′) are both hydrogen.

In some embodiments, B is thiazolyl.

In some embodiments, m is 1.

In some embodiments, R¹ is aryl (e.g., phenyl).

In some embodiments, in is 2.

In some embodiments, two R¹, together with the atoms to which they areattached, form an aryl ring. In some embodiments, the aryl ring issubstituted with —C(Y)R^(e). In some embodiments, Y is O. In someembodiments, R^(e) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, B is:

In some embodiments, B is:

In some embodiments, E is aryl (e.g., phenyl).

In some embodiments, n is 1.

In some embodiments, R² is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R² is C₁-C₈ alkyl substituted with 1-3 R⁶. In someembodiments, R² is C₁ alkyl substituted with 1 R⁶.

In some embodiments, R⁶ is —NR^(b)R^(b′). In some embodiments, R^(b) andR^(b′) are each independently C₁-C₈ alkyl (e.g., R^(b) and R^(b′) areboth methyl, or R^(b) and R^(b′) are both ethyl). In some embodiments,one of R^(b) and R^(b′) is hydrogen and the other is haloalkyl (e.g.,trifluoroethyl).

In some embodiments, R⁶ is —OR^(d). In some embodiments, R^(d) is cyclyl(e.g., cyclopentyl). In some embodiments, R^(d) is heterocyclylalkyl(e.g., —CH₂-tetrahydropyranyl).

In some embodiments, R² is C₂ alkyl substituted with 1 R⁶.

In some embodiments, R⁶ is —C(Y)NR^(b)R^(b′). In some embodiments, Y isO. In some embodiments, R^(b) and R^(b′) are both hydrogen. In someembodiments, R^(b) and R^(b′) are each independently C₁-C₈ alkyl (e.g.,R^(b) and R^(b′) are both methyl). In some embodiments, one of R^(b) andR^(b′) is hydrogen and the other is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R⁶ is —C(Y)R^(e). In some embodiments, Y is O. Insome embodiments, R^(e) is heterocyclyl (e.g., morpholino orthiomorpholino). In some embodiments, R^(e) is thiomorpholinosubstituted with 2 R⁶. In some embodiments, each R⁶ is oxo. In someembodiments, R^(e) is:

In some embodiments, R² is C₃ alkyl substituted with 1 R⁶.

In some embodiments, R⁶ is —C(Y)NR^(b)R^(b′). In some embodiments, Y isO. In some embodiments, R^(b) and R^(b′) are both hydrogen. In someembodiments, R^(b) and R^(b′) are each independently C₁-C₈ alkyl (e.g.,R^(b) and R^(b′) are both methyl). In some embodiments, one of R^(b) andR^(b′) is hydrogen and the other is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R⁶ is —NR^(c)C(Y)R^(c′). In some embodiments, Y isO. In some embodiments, R^(c) and R^(c′) are each independently C₁-C₈alkyl (e.g., R^(c) and R^(c′) are both methyl).

In some embodiments, R⁶ is —OR^(d). In some embodiments, R^(d) ishydrogen. In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R⁶ is silyloxy (e.g., tert-butyldimethylsilyloxy).

In some embodiments, R⁶ is —C(Y)R^(e). In some embodiments. Y is O. Insome embodiments, R^(e) is heterocyclyl (e.g., morpholino).

In some embodiments, R² is (C₂-C₈ alkynyl. In some embodiments, R² isC₂-C₈ alkynyl substituted with 1 R⁶ (e.g., C₃ alkynyl substituted with 1R⁶). In some embodiments, R² is —C≡C—CH₂—R⁶. In some embodiments, R⁶ is—NR^(b)R^(b′). In some embodiments, R^(b) and R^(b′) are eachindependently C₁-C₈ alkyl (e.g., R^(b) and R^(b′) are both methyl). Insome embodiments, R⁶ is —OR^(d). In some embodiments, R^(d) is hydrogen.In some embodiments, R⁶ is silyloxy (e.g., tert-butyldimethylsilyloxy).In some embodiments, R⁶ is heterocyclyl (e.g., morpholino orthiomorpholino). In some embodiments, R⁶ is thiomorpholino substitutedwith 2 R⁷. In some embodiments, each R⁷ is oxo. In some embodiments, R⁶is:

In some embodiments, R² is aryl (e.g., phenyl). In some embodiments, R²is unsubstituted phenyl.

In some embodiments, R² is phenyl substituted with 1 R⁶.

In some embodiments, R⁶ is heterocyclylalkyl (e.g., —CH₂-morpholino). Insome embodiments, R⁶ is haloalkyl (e.g., trifluoromethyl). In someembodiments, R⁶ is —CN. In some embodiments, R⁶ is —OR^(d). In someembodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl). In some embodiments,R⁶ is —C(Y)R^(e). In some embodiments, Y is O. In some embodiments,R^(e) is heterocyclyl (e.g., morpholino).

In some embodiments, R² is phenyl substituted with 2 R⁶.

In some embodiments, each R⁶ is independently —OR^(d). In someembodiments, each R^(d) is C₁-C₈ alkyl (e.g., methyl). In someembodiments, one R⁶ is halo (e.g., fluoro) and the other is C₁-C₈ alkyl(e.g., methyl). In some embodiments, one R⁶ is —C(O)OR^(a) and the otheris —OR^(d). In some embodiments, R^(a) and R^(d) are each independentlyC₁-C₈ alkyl (e.g., R^(a) and R^(d) are both methyl).

In some embodiments, R² is heteroaryl.

In some embodiments, R² is isoxazolyl. In some embodiments, R² isisoxazolyl substituted with 2 R⁶. In some embodiments, each R⁶ isindependently C₁-C₈ alkyl (e.g., R⁶ is methyl).

In some embodiments, R² is pyrazolyl. In some embodiments, R² ispyrazolyl substituted with 1 R⁶. In some embodiments, R⁶ is C₁-C₈ alkyl(e.g., methyl).

In some embodiments, R² is pyridyl. In some embodiments, R⁶ isunsubstituted pyridyl. In some embodiments, R² is pyridyl substitutedwith 1 R⁶. In some embodiments, R⁶ is halo (e.g., fluoro). In someembodiments, R⁶ is —NR^(b)R^(b′). In some embodiments, R^(b) and R^(b′)are each hydrogen. In some embodiments, R⁶ is —OR^(d). In someembodiments, R^(d) is hydrogen. In some embodiments, R^(d) is C₁-C₈alkyl (e.g., methyl). In some embodiments, R⁶ is heterocyclyl (e.g.,morpholino or piperazinyl). In some embodiments, R⁶ is piperazinylsubstituted with 1 R⁷. In some embodiments, R⁷ is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, R² is pyrimidinyl.

In some embodiments, R² is pyridazinyl.

In some embodiments, R² is cyclyl (e.g., cyclopropyl).

In some embodiments, R² is heterocyclyl (e.g., morpholino orpyrrolidinyl).

In some embodiments, R² is aralkyl (e.g., benzyl).

In some embodiments, R² is heterocyclylalkyl. In some embodiments, thealkyl is C₁ alkyl. In some embodiments, the alkyl is C₂ alkyl. In someembodiments, the alkyl is C₃ alkyl. In some embodiments, theheterocyclyl is piperidinyl. In some embodiments, the heterocyclyl ispiperazinyl. In some embodiments, the heterocyclyl is piperazinylsubstituted with 1 R⁶. In some embodiments, R⁶ is C₁-C₈ alkyl (e.g.,methyl). In some embodiments, the heterocyclyl is pyrrolidinyl. In someembodiments, the heterocyclyl is morpholino. In some embodiments, theheterocyclyl is thiomorpholino. In some embodiments, the heterocyclyl isthiomorpholino substituted with 2 R⁶. In some embodiments, each R⁶ isoxo. In some embodiments, the heterocyclyl is:

In some embodiments, R² is halo (e.g., fluoro, chloro, bromo or iodo).

In some embodiments, R² is haloalkyl (e.g., trifluoromethyl).

In some embodiments, R² is haloalkoxy (e.g., trifluoromethoxy).

In some embodiments, R² is —CN.

In some embodiments, R² is —NO₂.

In some embodiments, R² is —C(O)OR^(a). In some embodiments, R^(a) ishydrogen. In some embodiments, R^(a) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R² is —C(Y)NR^(b)R^(b′). In some embodiments, Y isO. In some embodiments, R^(b) and R^(b′) are each hydrogen. In someembodiments, R^(b) and R^(b′) are each independently C₁-C₈ alkyl (e.g.,R^(b) and R^(b′) are both methyl). In some embodiments, one of R^(b) andR^(b′) is hydrogen and the other is C₁-C₈ alkyl (e.g., methyl or ethyl).In some embodiments, the C₁-C₈ alkyl is ethyl substituted with 2 R⁶. Insome embodiments, each R¹ is independently —OR^(d). In some embodiments,each R^(d) is C₁-C₈ alkyl (e.g., each R^(d) is methyl). In someembodiments, one of R^(b) and R^(b′) is hydrogen and the other isheterocyclylalkyl (e.g., —CH₂—CH₂-morpholino). In some embodiments, oneof R^(b) and R^(b′) is hydrogen and the other is haloalkyl (e.g.,trifluoroethyl).

In some embodiments, R² is —NR^(b)R^(b′). In some embodiments, R^(b) andR^(b′) are both hydrogen. In some embodiments, R^(b) and R^(b′) are eachindependently C₁-C₈ alkyl (e.g., R^(b) and R^(b′) are both methyl). Insome embodiments, one of R^(b) and R^(b′) is hydrogen and the other isC₁-C₈ alkyl (e.g., methyl). In some embodiments, one of R^(b) and R^(b′)is hydrogen and the other is heterocyclyl (e.g., tetrahydropyranyl). Insome embodiments, one of R^(b) and R^(b′) is hydrogen and the other isheterocyclylalkyl. In some embodiments, the alkyl is C₁ alkyl. In someembodiments, the alkyl is C₂ alkyl. In some embodiments, the alkyl is C₃alkyl. In some embodiments, the heterocyclyl is morpholino. In someembodiments, the heterocyclyl is pyrrolidinyl. In some embodiments, theheterocyclyl is tetrahydrofuranyl. In some embodiments, the heterocyclylis tetrahydropyranyl. In some embodiments, one of R^(b) and R^(b′) ishydrogen and the other is hydroxyalkyl. In some embodiments, the alkylis C₂ alkyl. In some embodiments, one of R^(b) and R^(b′) is hydrogenand the other is alkoxyalkyl. In some embodiments, the alkyl is C₂alkyl. In some embodiments, the alkyl is C₃ alkyl. In some embodiments,the alkoxy is methoxy. In some embodiments, one of R^(b) and R^(b′) ishydrogen and the other is —C(Y)R^(e). In some embodiments, Y is O. Insome embodiments, R^(e) is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R^(e) is heterocyclyl. In some embodiments, R^(e) istetrahydropyranyl.

In some embodiments, R² is —OR^(d),

In some embodiments, R^(d) is hydrogen. In some embodiments, R^(d) isC₁-C₈ alkyl (e.g., methyl). In some embodiments, R^(d) is methylsubstituted with 1 R⁶. In some embodiments, R⁶ is —C(Y)R^(e). In someembodiments, Y is O. In some embodiments, R^(e) is heterocyclyl (e.g.,morpholino). In some embodiments, R⁶ is —C(Y)NR^(b)R^(b′). In someembodiments, Y is O. In some embodiments, R^(b) and R^(b′) are eachindependently C₁-C₈ alkyl (e.g., R^(b) and R^(b′) are both methyl orR^(b) and R^(b′) are both ethyl). In some embodiments, one of R^(b) andR^(b′) is hydrogen and the other is C₁-C₈ alkyl (e.g., methyl or ethyl).

In some embodiments, R^(d) is ethyl. In some embodiments, R^(d) is C₃alkyl (e.g., isopropyl or n-propyl). In some embodiments, R^(d) isoptionally substituted heteroaralkyl. In some embodiments, R^(d) isoptionally substituted pyrindinalkyl.

In some embodiments, R^(d) is n-propyl substituted with 1 R⁶. In someembodiments, R⁶ is —NR^(c)C(Y)R^(c′). In some embodiments, Y is O. Insome embodiments, R^(c) and R^(c′) are each independently C₁-C₈ alkyl(e.g., R^(c) and R^(c′) are both methyl). In some embodiments, R^(d) iscyclyl (e.g., cyclopentyl).

In some embodiments, R^(d) is heteroaralkyl (e.g., —CH₂-pyridyl). Insome embodiments, the pyridyl is substituted with 1 R^(d). In someembodiments, R⁶ is alkyl (e.g., methyl) or haloalkyl (e.g., CF). In someembodiments, R⁶ is —OR^(d). In some embodiments, R^(d) is C₁-C₈ alkyl(e.g., methyl).

In some embodiments, R^(d) is heterocyclylalkyl. In some embodiments,the alkyl is C₁ alkyl. In some embodiments, the alkyl is C₂ alkyl. Insome embodiments, the alkyl is C₃ alkyl. In some embodiments, the alkylis C₄ alkyl. In some embodiments, the heterocyclyl is morpholino. Insome embodiments, the heterocyclyl is piperidinyl. In some embodiments,the heterocyclyl is tetrahydrofuranyl. In some embodiments, R^(d) iscyclylalkyl (e.g., —CH₂-cyclobutyl).

In some embodiments, R^(d) is alkoxyalkyl. In some embodiments, thealkyl is C₂ alkyl. In some embodiments, the alkyl is C₃ alkyl. In someembodiments, the alkoxy is methoxy.

In some embodiments, R^(d) is dialkylaminoalkyl. In some embodiments,the alkyl is C₂ alkyl. In some embodiments, the alkyl is C₃ alkyl. Insome embodiments, the dialkylamino is dimethylamino.

In some embodiments, R² is —C(Y)R^(e). In some embodiments, Y is O. Insome embodiments, R^(e) is heterocyclyl. In some embodiments, R^(e) ispiperidinyl. In some embodiments, R^(e) is pyrrolidinyl. In someembodiments, R^(e) is piperazinyl. In some embodiments, R^(e) ispiperazinyl substituted with 1 R⁶. In some embodiments, R⁶ is C₁-C₈alkyl (e.g., methyl). In some embodiments, R^(e) is morpholino. In someembodiments, R^(e) is thiomorpholino. In some embodiments, R^(e) isthiomorpholino substituted with 2 R⁶. In some embodiments, each R⁶ isoxo. In some embodiments, R^(e) is:

In some embodiments, n is 2.

In some embodiments, each R² is independently halo (e.g., each R² ischloro).

In some embodiments, each R² is independently —OR^(d).

In some embodiments, each R^(d) is C₁-C₈ alkyl.

In some embodiments, each R² is methoxy. In some embodiments, one R² ismethoxy and the other is ethoxy. In some embodiments, one R² is methoxyand the other is propoxy. In some embodiments, one R² is methoxy and theother is isopropoxy.

In some embodiments, one R² is methoxy and the other is ethoxysubstituted with 1 R⁶. In some embodiments, R⁶ is —NR^(b)R^(b′). In someembodiments, R^(b) and R^(b′) are each independently C₁-C₈ alkyl (e.g.,R^(b) and R^(b′) are both methyl). In some embodiments, R⁶ is —OR^(d).In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R² is methoxy and the other is propoxysubstituted with 1 R⁶. In some embodiments, R⁶ is —OR^(d). In someembodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R¹ is —OR^(d) and the other is C₁-C₈ alkyl(e.g., methyl). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methylor ethyl).

In some embodiments, one R² is —OR^(d) and the other is halo (e.g.,chloro). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R² is —OR^(d) and the other is —CN. In someembodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R¹ is —OR^(d) and the other is —C(O)OR^(a). Insome embodiments, R^(d) and R^(a) are both hydrogen.

In some embodiments, one R² is —OR^(d) and the other is C₁-C₈ alkyl(e.g., methyl). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, one R¹ is —OR^(d) and the other is —C(Y)R^(e). Insome embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl). In someembodiments, Y is O. In some embodiments, R^(e) is heterocyclyl (e.g.,morpholino).

In some embodiments, one R² is halo (e.g., chloro or bromo) and theother is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R² is C₁-C₈ alkyl (e.g., methyl) and the otheris —CN.

In some embodiments, one R² is C₁-C₈ alkyl (e.g., methyl) and the otheris heteroaryl (e.g., pyridyl). In some embodiments, the pyridyl issubstituted with 1 R⁶. In some embodiments, R⁶ is —OR^(d). In someembodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, one R² is C₁-C₈ alkyl (e.g., methyl) and the otheris heterocyclylalkyl (e.g., —CH₂-morpholino).

In some embodiments, p is 0.

In some embodiments, p is 1.

In some embodiments, R³ is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R³ is halo (e.g., chloro). In some embodiments, R³ ishaloalkyl (e.g., trifluoromethyl). In some embodiments. R³ is oxo.

In some embodiments, R³ is —OR^(d). In some embodiments, R^(d) ishydrogen. In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R³ is —NR^(b)R^(b′). In some embodiments, R^(b) andR^(b′) are both hydrogen. In some embodiments, one of R^(b) and R^(b′)is hydrogen and the other is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R³ is heterocyclyl (e.g., piperazinyl). In someembodiments, R³ is piperazinyl substituted with 1 R⁶. In someembodiments, R⁶ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, E is a 5-membered heteroaryl ring.

In some embodiments, E is a thiophene ring.

In some embodiments, E is a pyrrole ring.

In some embodiments, n is 1. In some embodiments, R² is C₁-C₈ alkyl(e.g., methyl). In some embodiments, E is an N-methylpyrrole ring.

In some embodiments, L is NR⁵. In some embodiments, R⁵ is hydrogen.

In some embodiments, L is O.

In some embodiments, the compound is:

In some embodiments, R² is C₁-C₄ alkoxy. In some embodiments, R² ishalo. In some embodiments, R¹ is —C(Y)NR^(b)R^(b′),

In some embodiments, the compound is:

In some embodiments, R² is C₁-C₄ alkoxy. In some embodiments, R² ishalo. In some embodiments, R¹ is —C(Y)NR^(b)R^(b′).

In some embodiments, L and

In some embodiments, L and

In some embodiments, L is NH, and

is selected from

In some embodiments R⁶ is halo. In some embodiments, R^(b) or R^(b′) aredisubstituted with R⁶ (e.g., dichloro, 4-fluoro, 3-chloro, or difluoro).

In some embodiments, the compound is:

In some embodiments, R¹ is —C(Y)NR^(b)R^(b′). In some embodiments, R¹ ishalo. In some embodiments, R² is C₁-C₄ alkoxy. In some embodiments, R²is halo. In some embodiments, in is 2 and two R¹ are 3,4-dichloro;3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro,4-fluoro; or3-chloro,5-fluoro. In some embodiments, R² is —C(O)NR^(b)R^(b′) and R³is H. In some embodiments, R^(b) and R^(b′) are H. In some embodiments,R^(b) and R^(b′) are independently C₁-C₄ alkyl or halo-substituted C₁-C₄alkyl. In some embodiments, R^(b) is methyl and R^(b′) istrifluoroethyl. In some embodiments, R¹ is C₁-C₄ alkoxy orhalo-substituted C₁-C₄ alkoxy. In some embodiments, n and p are zero.

In some embodiments, the compound is:

In some embodiments, R¹ is —C(Y)NR^(b)R^(b′). In some embodiments, R¹ ishalo. In some embodiments, R² is C₁-C₄ alkoxy. In some embodiments, R²is halo. In some embodiments, m is 2 and two R¹ are 3,4-dichloro;3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro,4-fluoro; or3-chloro,5-fluoro. In some embodiments, R² is —C(O)NR^(b)R^(b′) and R³is H. In some embodiments, R^(b) and R^(b′) are H. In some embodiments,R^(b) and R^(b′) are independently C₁-C₄ alkyl or halo-substituted C₁-C₄alkyl. In some embodiments, R^(b) is methyl and R^(b′) istrifluoroethyl. In some embodiments, R¹ is C₁-C₄ alkoxy orhalo-substituted C₁-C₄ alkoxy. In some embodiments, n and p are zero.

In some embodiments, the compound is:

In some embodiments, R¹ is —C(Y)NR^(b)R^(b′). In some embodiments, R¹ ishalo. In some embodiments, R² is C₁-C₄ alkoxy. In some embodiments, R²is halo. In some embodiments, m is 2 and two R¹ are 3,4-dichloro;3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro,4-fluoro; or3-chloro,5-fluoro. In some embodiments, R² is —-C(O)NR^(b)R^(b′) and R³is H. In some embodiments, R^(b) and R^(b′) are H. In some embodiments,R^(b) and R^(b′) are independently C₁-C₄ alkyl or halo-substituted C₁-C₄alkyl. In some embodiments, R^(b) is methyl and R^(b′) istrifluoroethyl. In some embodiments, R¹ is C₁-C₄ alkoxy orhalo-substituted C₁-C₄ alkoxy. In some embodiments, n and p are zero.

In some embodiments, the compound is:

In some embodiments, R¹ is —C(Y)NR^(b)R^(b′). In some embodiments, R¹ ishalo. In some embodiments, R² is C₁-C₄ alkoxy. In some embodiments, R²is halo. In some embodiments, m is 2 and two R¹ are 3,4-dichloro;3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro,4-fluoro; or3-chloro,5-fluoro. In some embodiments, R² is —C(O)NR^(b)R^(b′) and R³is H. In some embodiments, R^(b) and R^(b′) are H. In some embodiments,R^(b) and R^(b′) are independently C₁-C₄ alkyl or halo-substituted C₁-C₄alkyl. In some embodiments, R^(b) is methyl and R^(b′) istrifluoroethyl. In some embodiments, R¹ is C₁-C₄ alkoxy orhalo-substituted C₁-C₄ alkoxy. In some embodiments, n and p are zero.

Compounds of Formula (V)

The following aspects and embodiments relate to compounds of formula(V), corresponding to formula (I) of U.S. Provisional Patent ApplicationNo. 61/291,550, entitled “Therapeutic Compounds and Related Methods ofUse” filed on Dec. 31, 2009, and incorporated herein by reference in itsentirety.

-   Item 40, A compound of formula (V):

wherein:

L is CR⁴R⁵, O, C(O), NR⁶C(O), or NR⁷;

A is CR⁸, CH or N;

each X¹, X², X³, X⁴ and X⁵ is independently CH or N, provided that atleast two of X¹, X², X³, X⁴ and X⁵ are N;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3;

R¹ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, heteroaryl,cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl orheterocyclylalkyl, each of which may be optionally substituted with 1-5R⁹; wherein R¹ or R⁹ may optionally be taken together with one of R⁴,R⁵, R⁶ or R⁷, and the atoms to which they are attached, to form acyclyl, heterocyclyl, aryl or heteroaryl ring that is optionallysubstituted with 1-3 R¹⁰;

each R² and R³ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f); each of which is optionally substituted with 1-3 R¹¹;

each R⁴, R⁵, R⁶ and R⁷ is independently H, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl,heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a), —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f);

each R⁴, R⁵, R⁶ and R⁷ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl,heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, oxo, thiono, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which may be optionally further substituted;wherein two R⁸, two R⁹, two R¹⁰ or two R¹¹ may optionally be takentogether with the atoms to which they are attached to form an optionallysubstituted cyclyl, heterocyclyl, aryl or heteroaryl ring;

each Y is independently O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl,cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of whichmay be optionally substituted with 1-3 R⁸,

or a pharmaceutically acceptable derivative or prodrug thereof.

In some embodiments, A is CH. In some embodiments, A is N.

In some embodiments, L is NR⁷. In some embodiments, R⁷ is H.

In some embodiments, R¹ is aryl (e.g., phenyl).

In some embodiments, R¹ is phenyl substituted with 1 R⁹. In someembodiments, R¹ is phenyl substituted with 1 R⁹ in the ortho position.In some embodiments, R¹ is phenyl substituted with 1 R⁹ in the metaposition. In some embodiments, R⁹ is haloalkoxy (e.g., difluoromethoxyor trifluoromethoxy). In some embodiments, R⁹ is —CN. In someembodiments, R⁹ is —C(O)OR^(a). In some embodiments, R¹ is hydrogen. Insome embodiments, R⁹ is —C(Y)NR^(b)R^(b′). In some embodiments, Y is O.In some embodiments, R^(b) and R^(b′) are both hydrogen. In someembodiments, R¹ is:

In some embodiments, one of R^(b) and R^(b′) is hydrogen and the otheris C₁-C₈ alkyl (e.g., methyl),

In some embodiments, R¹ is phenyl substituted with 2 R⁹. In someembodiments, each R⁹ is independently halo (e.g., each R⁹ is fluoro oreach R⁹ is chloro). In some embodiments, one R⁹ is fluoro and the otheris chloro. In some embodiments, one R⁹ is halo (e.g., chloro) and theother is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy).

In some embodiments, 2 R⁹ are taken together with the atoms to whichthey are attached to form a heterocyclyl ring, e.g., a 5-memberedheterocyclyl ring (e.g., a dioxole ring). In some embodiments, thedioxole ring is unsubstituted. In some embodiments, the dioxole ring issubstituted. In some embodiments, the dioxole ring is substituted withtwo fluoro substituents. In some embodiments, R¹ is selected from:

In some embodiments, R¹ is aralkyl (e.g., benzyl). In some embodiments,R¹ is aralkyl substituted with 2 R⁹ (e.g., benzyl substituted with 2R⁹). In some embodiments, 2 R⁹ substituents are on the phenyl ring. Insome embodiments, each R⁹ is independently halo (e.g., each R⁹ ischloro).

In some embodiments, R¹ is alkyl (e.g., methyl).

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, R² is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R² is C₁-C₈ alkyl substituted with 1 R¹¹ (e.g., methylsubstituted with 1 R¹¹). In some embodiments, R¹¹ is heterocyclyl (e.g.,morpholino).

In some embodiments, R² is aryl (e.g., phenyl). In some embodiments, R²is phenyl substituted with 1 R¹¹. In some embodiments, R¹¹ is —CN. Insome embodiments, R¹¹ is —OR^(d). In some embodiments, R^(d) is C₁-C₈alkyl (e.g., methyl). In some embodiments, R¹¹ is halo.

In some embodiments, R² is halo (e.g., fluoro, chloro, bromo or iodo).

In some embodiments, R² is —NR^(c)C(Y)R^(c′). In some embodiments, R^(c)is hydrogen. In some embodiments, Y is O. In some embodiments, R^(c′) isalkyl (e.g., methyl). In some embodiments, R^(c′) is aryl (e.g.,phenyl). In some embodiments, R^(c′) is phenyl substituted with 1 R⁸. Insome embodiments, R⁸ is —OR^(d). In some embodiments, R^(d) is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R^(c′) is heteroaryl. In some embodiments, R^(c′)is furanyl. In some embodiments, R^(c) is pyridyl. In some embodiments,R^(c′) is pyridyl substituted with 1 R⁸. In some embodiments, R⁸ is—OR^(d). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R^(c′) is cyclyl (e.g., cyclohexyl). In someembodiments, R^(c′) is cyclohexyl substituted with 1 R⁸. In someembodiments, R⁸ is —OR^(d). In some embodiments, R^(d) is C₁-C₈ alkyl(e.g., methyl).

In some embodiments, R^(c′) is heterocyclyl (e.g., tetrahydropyranyl).

In some embodiments, R¹ is —NR^(b)R^(b′). In some embodiments, R^(b) andR^(b′) are both hydrogen. In some embodiments, R^(b) and R^(b′) are eachindependently C₁-C₈ alkyl (e.g., R^(b) and R^(b′) are both methyl).

In some embodiments, R² is —OR^(d). In some embodiments, R^(d) is C₁-C₈alkyl (e.g., methyl or ethyl). In some embodiments, R^(d) is ethylsubstituted with 1 R⁸. In some embodiments, R⁸ is —OR^(d). In someembodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl). In some embodiments,R² is —OCH₂CH₂OCH₃. In some embodiments, R² is —OCH₂CH₂OCH₂CH₂CH₃. Insome embodiments, R² is —OCH₂CH₂OCH₂CH₂OCH₃.

In some embodiments, n is 2.

In some embodiments, one R² is C₁-C₈ alkyl (e.g., methyl) and the otheris halo (e.g., chloro).

In some embodiments, one R² is —OR^(d) and the other is halo (e.g.,chloro). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, X¹ and X⁴ are N and X², X³ and X⁵ are CH.

In some embodiments, X¹ and X³ are N and X², X⁴ and X⁵ are CH.

In some embodiments, X² and X³ are N and X¹, X⁴ and X⁵ are CH.

In some embodiments, X² and X⁴ are N and X¹, X³ and X⁵ are CH.

In some embodiments, the compound is:

wherein s is 0, 1, 2, 3 or 4.

In some embodiments, R⁹ is —C(O)NH₂, C₁-C₄ alkoxy, or substituted C₁-C₄alkoxy. In some embodiments, R⁹ is halo,

In some embodiments, the compound is:

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, R₁ is heteroaralkyl (e.g.,—CH₂-pyridyl). In some embodiments, LR¹ is NH(CH₃).

In some embodiments, the compound is:

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, R₁ is heteroaralkyl (e.g.,—CH₂-pyridyl). In some embodiments, LR¹ is NH(CH₃).

In some embodiments, the compound is:

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, R₁ is heteroaralkyl (e.g.,—CH₂-pyridyl). In some embodiments, LR¹ is NH(CH₃).

In some embodiments, the compound is:

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, R₁ is heteroaralkyl (e.g.,—CH₂-pyridyl). In some embodiments, LR¹ is NH(CH₃).

In some embodiments, the compound is:

wherein t is 1-3.

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, R₁ is heteroaralkyl (e.g.,—CH₂-pyridyl). In some embodiments, LR¹ is NH(CH₃). In some embodiments,R¹¹ is independently halo, nitrile, C₁-C₄ alkoxy, —C(O)NH₂, hydroxy, orC₁-C₄ hydroxyalkyl. In some embodiments, R¹¹ is fluoro. In someembodiments, R¹¹ is methoxy, ethoxy, or methoxyethoxy ether. In someembodiments, R¹¹ is —OCH₂CH₂OCH₃. In some embodiments, R¹¹ is—OCH₂CH₂OCH₂CH₃. In some embodiments, R¹¹ is —OCH₂CH₂OCH₂CH₂OCH₃.

In some embodiments, the compound is:

N wherein t is 1-3.

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, LR¹ is NH(CH₃). In some embodiments,R¹¹ is independently halo, nitrile, C₁-C₄ alkoxy, —C(O)NH₂, hydroxy, orC₁-C₄ hydroxyalkyl. In some embodiments, R¹¹ is fluoro. In someembodiments, R¹¹ is methoxy, ethoxy, or methoxyethoxy ether. In someembodiments, R¹¹ is —OCH₂CH₂OCH₃. In some embodiments, R¹¹ is—OCH₂CH₂OCH₂CH₂CH₃. In some embodiments, R¹¹ is —OCH₂CH₂OCH₂CH₂OCH₃.

In some embodiments, the compound is:

wherein t is 1-3.

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, LR¹ is NH(CH₃). In some embodiments,R¹¹ is independently halo, nitrile, C₁-C₄ alkoxy, —C(O)NH₂, hydroxy, orC₁-C₄ hydroxyalkyl. In some embodiments, R¹¹ is fluoro. In someembodiments, R¹¹ is methoxy, ethoxy, or methoxyethoxy ether. In someembodiments, R¹¹ is —OCH₂CH₂OCH₃. In some embodiments, R¹¹ is—OCH₂CH₂OCH₂CH₂CH₃. In some embodiments, R¹¹ is —OCH₂CH₂OCH₂CH₂OCH₃.

In some embodiments, the compound is:

wherein t is 1-3.

In some embodiments, R₁ is selected from methyl, cyclohexyl, t-butyl,and pyridinyl. In some embodiments, LR¹ is NH(CH₃). In some embodiments,R¹¹ is independently halo, nitrile, C₁-C₄ alkoxy, —C(O)NH, hydroxy, orC₁-C₄ hydroxyalkyl. In some embodiments, R¹¹ is fluoro. In someembodiments, R¹¹ is methoxy, ethoxy, or methoxyethoxy ether. In someembodiments, R¹¹ is —OCH₂CH₂OCH₃. In some embodiments, R¹¹ is—OCH₂CH₂OCH₂CH₂CH₃. In some embodiments, R¹¹ is —OCH₂CH₂OCH₂CH₂OCH₃.

Compounds of Formula (VI)

The following aspects and embodiments relate to compounds of formula(VI) corresponding to formula (I) of U.S. Provisional Patent ApplicationNo. 61/291,554, entitled “Therapeutic Compounds and Related Methods ofUse” filed on Dec. 31, 2009, and incorporated herein by reference in itsentirety.

-   Item 41. A compound of formula (VI):

wherein:

A is CR⁵, CH or N;

L is O or NR⁶;

1, 2 or 3 of X¹, X², X³, X⁴ and X⁵ are N and the others are CH;

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3 or 4;

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, cyclyl orheterocyclyl, each of which is optionally substituted with 1-3 R⁷; orwhen L is NR⁶, R¹ or R⁷ may be taken together with R⁶ and the atoms towhich they are attached to form a heterocyclyl or heteroaryl ring thatis optionally substituted with 1-3 R⁸;

R² is aryl or heteroaryl, each of which is optionally substituted with1-5 R⁹;

each R³, R⁴ and R⁵ is independently C₁-C₈ alkyl, C₁-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹⁰;

R⁶ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, cyclyl orheterocyclyl, each of which is optionally substituted with 1-3 R¹¹;

each R⁷, R⁸, R⁹ and R¹⁰ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl,heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy,silylalkoxyalkyl, oxo, thiono, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′), —OC(O)NR^(b)R^(b′),—NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′), —NR^(c)SO₂R^(c′),—NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e) or—S(O)_(q)R^(f), each of which is optionally substituted with 1-3 R¹²;wherein two R⁷, two R⁸, two R⁹ or two R¹⁰ may optionally be takentogether with the atoms to which they are attached to form an optionallysubstituted cyclyl, heterocyclyl, aryl or heteroaryl ring;

each R¹¹ and R¹² is independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl,cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy,silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO₂,—C(O)OR^(a), —C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —NR^(b)R^(b′),—OC(O)NR^(b)R^(b′), —NR^(c)C(O)OR^(c′), —SO₂NR^(b)R^(b′),—NR^(c)SO₂R^(c′), —NR^(c)C(Y)NR^(b)R^(b′), —OR^(d), —SR^(d′), —C(Y)R^(e)or —S(O)_(q)R^(f);

each Y is independently O or S;

q is 1 or 2; and

each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(d′), R^(e) and R^(f)is independently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl,cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of whichmay be optionally substituted with 1-3 R⁷;

or a pharmaceutically acceptable derivative or prodrug thereof, whereinwhen R¹ is cyclopropyl, R⁹ is not

In some embodiments, R⁷ is not:

In some embodiments, R¹ is C₁-C₈ alkyl, which is optionally substitutedwith 1-3 R⁷; or when L is NR⁶, R¹ and R⁶ may be taken together with theatoms to which they are attached to form a heterocyclyl or heteroarylring that is optionally substituted with 1-3 R⁸.

In some embodiments, A is CH. In some embodiments, A is N.

In some embodiments, L is NR⁶. In some embodiments, R⁶ is hydrogen.

In some embodiments, R¹ is C₁-C₈ alkyl, e.g., methyl, ethyl, C₃ alkyl(e.g., n-propyl or isopropyl), C₄ alkyl (e.g., n-butyl, isobutyl ortert-butyl), or C₅ alkyl (e.g., pentan-3-yl).

In some embodiments, R¹ is C₁-C₈ alkyl substituted with 1-3 R⁷ (e.g.,C₁-C₈ alkyl substituted with 1 R⁷). In some embodiments, R¹ is methylsubstituted with 1 R⁷. In some embodiments, R⁷ is cyclyl (e.g.,cyclopropyl). In some embodiments, R⁷ is aryl (e.g., phenyl).

In some embodiments, R¹ is ethyl substituted with 1 R⁷. In someembodiments, R⁷ is aryl (e.g., phenyl). In some embodiments, R⁷ is—OR^(d). In some embodiments, R^(d) is aryl (e.g., phenyl).

In some embodiments, R¹ is n-propyl substituted with 1 R⁷. In someembodiments, R¹ is —OR^(d). In some embodiments, R^(d) is C₁-C₈ alkyl(e.g., C₃ alkyl, e.g., n-propyl).

In some embodiments, R¹ is C₁-C₈ alkyl substituted with 3 R⁷. In someembodiments, R¹ is ethyl substituted with 3 R⁷. In some embodiments,each R¹ is independently halo (e.g., each R¹ is fluoro). In someembodiments, R¹ is 2,2,2-trifluoroethyl.

In some embodiments, R¹ is C₂-C₈ alkenyl, e.g., C₃ alkenyl (e.g.,—CH₂—CH═CH₂).

In some embodiments, R¹ is C₂-C₈ alkynyl, e.g., C₃ alkynyl (e.g.—CH₂—C≡CH).

In some embodiments, R¹ is cyclyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl). In some embodiments, the cyclyl group is abicyclic group (e.g., indanyl).

In some embodiments, R¹ is heterocyclyl (e.g., piperidyl). In someembodiments, R¹ is piperidyl substituted with 1 R⁷. In some embodiments,R⁷ is —C(Y)R^(e). In some embodiments, Y is O. In some embodiments,R^(e) is C₁-C₈ alkyl (e.g., methyl). In some embodiments, R¹ is —OR^(d).

In some embodiments, R⁶ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R¹ and R⁶ are taken together with the atoms towhich they are attached to form a heterocyclyl ring (e.g., a pyrrolidinering).

In some embodiments, R¹ and R⁶ are taken together with the atoms towhich they are attached to form a heteroaryl ring (e.g., an imidazolering).

In some embodiments, L is O.

In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R² is aryl (e.g., phenyl). In some embodiments, R²is unsubstituted phenyl. In some embodiments, R² is phenyl substitutedwith 1-3 R⁹. In some embodiments, R² is phenyl substituted with 1 R⁹.

In some embodiments, R² is:

In some embodiments, R⁹ is halo (e.g., fluoro or chloro). In someembodiments, R⁹ is —CN. In some embodiments, R⁹ is —NO₂. In someembodiments, R⁹ is haloalkoxy (e.g., trifluoroethoxy). In someembodiments, R⁹ is —NR^(b)R^(b′). In some embodiments, R^(b) and R^(b′)are each independently C₁-C₈ alkyl (e.g., R^(b) and R^(b′) are bothmethyl).

In some embodiments, R⁹ is —OR^(d). In some embodiments, R⁹ is—OCH₂CH₂OCH₃. In some embodiments, R⁹ is —OCH₂CH₂OCH₂CH₂CH₃. In someembodiments, R⁹ is —OCH₂CH₂OCH₂CH₂OCH₃. In some embodiments, R^(d) ishydrogen. In some embodiments, R^(d) is C₁-C₅ alkyl (e.g., methyl). Insome embodiments, R^(d) is methyl substituted with 1 R⁷. In someembodiments, R⁷ is —CYNR^(b)R^(b′). In some embodiments, Y is O andR^(b) and R^(b′) are each independently C₁-C₈ alkyl (e.g., R^(b) andR^(b′) are both methyl). In some embodiments, R^(d) is ethyl. In someembodiments, R^(d) is ethyl substituted with 1 R⁷. In some embodiments,R¹ is —OR^(d). In some embodiments, R^(d) is C₁-C₈ alkyl (e.g., methyl).In some embodiments, R⁷ is heterocyclyl (e.g., morpholino).

In some embodiments, R⁹ is hydroxyalkyl (e.g., —CH₂OH). In someembodiments, R⁹ is alkoxyalkyl (e.g., —CH₂—O—CH₃). In some embodiments,R⁹ is —C(O)R^(e). In some embodiments, R^(e) is heterocyclyl (e.g.,morpholino). In some embodiments, R⁹ is —S(O)_(q)R^(f). In someembodiments, q is 1. In some embodiments, R¹ is C₁-C₈ alkyl (e.g.,methyl).

In some embodiments, R² is phenyl substituted with 2 R⁹. In someembodiments, each R⁹ is independently halo (e.g., each R⁹ is fluoro). Insome embodiments, each R⁹ is independently —OR^(d). In some embodiments,each R^(d) is independently C₁-C₈ alkyl (e.g., each R^(d) is methyl).

In some embodiments, R² is heteroaryl. In some embodiments, R² is a6-membered heteroaryl. In some embodiments, R² is a 6-memberednitrogen-containing heteroaryl, e.g., pyridyl. In some embodiments, R²is unsubstituted pyridyl.

In some embodiments, R² is pyridyl substituted with 1 R⁹. In someembodiments, R⁹ is —OR^(d). In some embodiments, R^(d) is C₁-C₈ alkyl(e.g., methyl).

In some embodiments, R² is a 5-membered heteroaryl. In some embodiments,R² is a 5-membered nitrogen-containing heteroaryl (e.g., pyrrolyl oroxazolyl).

In some embodiments, m is 0.

In some embodiments, in is 1.

In some embodiments, R⁴ is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R⁴ is —OR^(d). In some embodiments, R^(d) is C₁-C₈ alkyl(e.g., methyl). In some embodiments, R⁴ is halo. In some embodiments, R⁴is methoxy. In some embodiments, R^(d) is C₁-C₈ alkyl.

In some embodiments, the compound has the following structure:

wherein one of X¹ and X² is N and the other is CHI.

In some embodiments, X¹ is CH and X² is N. In some embodiments, X¹ is Nand X² is CH. In some embodiments, the compound has the followingstructure:

In some embodiments, R² is aryl. In some embodiments, R² is heteroaryl.In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, the compound has the following structure:

In some embodiments, R² is aryl. In some embodiments, R² is heteroaryl.In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, the compound has the following structure:

In some embodiments, R² is aryl. In some embodiments, R² is heteroaryl.In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, the compound has the following structure:

wherein R¹ is C₁-C₈ alkyl, which is optionally substituted with 1-3 R⁷.

In some embodiments, R² is aryl. In some embodiments, R² is heteroaryl.In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, the compound has the following structure:

In some embodiments, R² is aryl. In some embodiments, R² is heteroaryl.In some embodiments, R¹ is C₁-C₈ alkyl (e.g., methyl).

In some embodiments, R² is

In some embodiments, the compound has the following structure:

In some embodiments, R² is aryl. In some embodiments, R² is heteroaryl.In some embodiments R¹ is C₁-C₈ alkyl (e.g., methyl). In someembodiments, R² is

In some embodiments, the compound has the following structure:

wherein p is 1, 2, 3, 4 or 5,

In some embodiments, L is NR⁶. In some embodiments, L is O. In someembodiments, R¹ is hydrogen or C₁-C₈ alkyl. In some embodiments, R^(j)is cyclyl or heterocyclyl. In some embodiments, R¹ is aralkyl orheteroaralkyl. In some embodiments, R¹ is methyl, cyclohexyl, t-butyl,or

In some embodiments, R¹ is hydrogen or C₁-C₈ alkyl.In some embodiments, R⁹ is C₁-C₈ alkyl, halo, —CN, or —OR^(d). In someembodiments, R³ is hydrogen.

In some embodiments, the compound has the following structure:

wherein p is 1, 2, 3, 4 or 5.

In some embodiments, L is NR⁶. In some embodiments, L is O. In someembodiments, R¹ is hydrogen or C₁-C₈ alkyl. In some embodiments, R¹ iscyclyl or heterocyclyl. In some embodiments, R¹ is aralkyl orheteroaralkyl. In some embodiments, R¹ is methyl, cyclohexyl, t-butyl,or

In some embodiments, R⁶ is hydrogen or C₁-C₈ alkyl. In some embodiments,R⁹ is C₁-C₈ alkyl, halo, —CN, or —OR^(d). In some embodiments, R³ ishydrogen.

Aspects and Embodiments of Compounds of Formulas (I), (II), (III), (IV),(V), and (VI)

In one aspect, the invention features a composition comprising acompound of formula (I), (II), (III), (IV), (V), or (VI) and anacceptable carrier.

In one aspect, the invention features a pharmaceutical compositioncomprising a compound of formula (I), (II), (III), (IV), (V), or (VI)and a pharmaceutically acceptable carrier.

In one aspect, the invention features a kit comprising a compositioncomprising a compound of formula (I), (II), (III), (IV), (V), or (VI)and an acceptable carrier.

In one aspect, the invention features a kit comprising a pharmaceuticalcomposition comprising a compound of formula (I), (II), (III), (IV),(V), or (VI) and a pharmaceutically acceptable carrier.

In one aspect, the invention features a dosage form comprising acomposition comprising a compound of formula (I), (II), (III), (IV),(V), or (VI) and an acceptable carrier.

In one aspect, the invention features a dosage form comprising apharmaceutical composition comprising a compound of formula (I), (II),(III), (IV), (V), or (VI) and a pharmaceutically acceptable carrier.

In one aspect, the invention features a method of treating a disorderthat would benefit by the modulation of STEP (e.g., by activation orinhibition of STEP) in a subject, the method comprising administering toa subject in need thereof a compound of formula (I), (II), (III), (IV),(V), or (VI). In one aspect, the invention features a method of treatinga disorder that would benefit by the inhibition of STEP, the methodcomprising administering to a subject in need thereof a compound offormula (I), (II), (III), (IV), (V), or (VI). In some embodiments, thedisorder is selected from schizophrenia, schizoaffective disorder,bipolar disorder, manic-depressive disorder, psychosis, mood and anxietydisorders, mania, drug or substance addiction, cognition disorders,learning disabilities, learning and memory disorders, aging andneurologic disorders associated with or linked with cognitiveimpairments; mild cognitive impairments (MCI), Alzheimer's disease,Alzheimer-related cognition disorders, Huntington's disease, Parkinson'sdisease, CADASIL syndrome (cerebral autosomal dominant arteriopathy withsubcortical infarcts and leukoencephalopathy), amnesia,Wernicke-Korsakoff syndrome, Korsakoff syndrome, mild traumatic headinjury (MBTI), traumatic head injury (TBI), fragile X syndrome, stroke,attention-deficit and hyperactivity disorder (ADHD), obsessivecompulsive disorder (OCD), post-traumatic stress disorder (PTSD), lossof concentration, autism, cerebral palsy, encephalopathy, andnarcolepsy. In some embodiments, the disorder affects learning andmemory, neurogenesis, neuronal plasticity, pain perception, mood andanxiety, or neuroendocrine regulation. In some embodiments, the disorderis a cognitive deficit disorder. In some embodiments, the disorderinvolves pain perception or neuroendocrine regulation. In someembodiments, the disorder affects the central nervous system. In someembodiments the disorder is selected from the group consisting ofschizophrenia; refractory, intractable or chronic schizophrenia;emotional disturbance; psychotic disorder; mood disorder; bipolar I typedisorder; bipolar II type disorder; depression; endogenous depression;major depression; melancholy and refractory depression; dysthymicdisorder; cyclothymic disorder; panic attack; panic disorder;agoraphobia; social phobia; obsessive-compulsive disorder;post-traumatic stress disorder; generalized anxiety disorder; acutestress disorder; hysteria; somatization disorder; conversion disorder;pain disorder; hypochondriasis; factitious disorder; dissociativedisorder; sexual dysfunction; sexual desire disorder; sexual arousaldisorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleepdisorder; adjustment disorder; alcohol abuse; alcohol intoxication; drugaddiction; stimulant intoxication; narcotism; anhedonia; iatrogenicanhedonia; anhedonia of a psychic or mental cause; anhedonia associatedwith depression; anhedonia associated with schizophrenia; delirium;cognitive impairment; cognitive impairment associated with Alzheimer'sdisease, Parkinson's disease and other neurodegenerative diseases;cognitive impairment caused by Alzheimer's disease; Parkinson's diseaseand associated neurodegenerative diseases; cognitive impairment ofschizophrenia; cognitive impairment caused by refractory, intractable orchronic schizophrenia; vomiting; motion sickness; obesity; migraine;pain (ache); mental retardation; autism disorder (autism); Tourette'sdisorder; tic disorder; attention-deficit/hyperactivity disorder;conduct disorder; and Down's syndrome.

In one aspect, the invention features a method of treating a conditionthat would benefit by the modulation of STEP (e.g., by activation orinhibition of STEP) in a subject, the method comprising administering toa subject in need thereof a compound of formula (I), (II), (III), (IV),(V), or (VI). In some embodiments, the condition is selected fromdecreased neurogenesis, cell resilience, or neuronal plasticity due tonormal aging, neurodegenerative disorders of the CNS; Alzheimer'sdisease, Huntington's disease, fragile X syndrome, amyotrophic lateralsclerosis/Lou Gehrig's disease, stroke, Parkinson's disease,parkinsonism, dementia, Pick disease, Corticobasal degeneration,Multiple system atrophy, Progressive supranuclear palsy, traumatic braininjury, head trauma, mild traumatic head injury (MBTI), traumatic headinjury (TBI), encephalopathy, intoxication related to ethanol,alcoholism, fetal alcohol syndrome, drug addiction or drug abuse.

In some embodiments, a compound of formula (I), (II), (III), (IV), (V),or (VI) is administered in combination with an additional therapeuticagent. In some embodiments, the additional therapeutic agent is anatypical antipsychotic. In some embodiments, the additional therapeuticagent is selected from the group consisting of aripiprazole, clozapine,ziprasidone, risperidone, quetiapine, olanzapine, amisulpride,asenapine, iloperidone, melperone, paliperidone, perospirone, sertindoleand sulpiride. In some embodiments, the additional therapeutic agent isa typical antipsychotic. In some embodiments, the additional therapeuticagent is selected from the group consisting of haloperidol, molindone,loxapine, thioridazine, molindone, thiothixene, pimozide, fluphenazine,trifluoperazine, mesoridazine, chlorprothixene, chlorpromazine,perphenazine, triflupromazine and zuclopenthixol.

DETAILED DESCRIPTION

A compound or composition described herein can be used, e.g., in amethod of treating schizophrenia or cognitive deficit. Many of thecompounds described herein modulate STEP activity and can be used, e.g.,to reduce or inhibit STEP activity, e.g., in a subject.

DEFINITIONS

The term “acyl” refers to an alkylcarbonyl, cycloalkylcarbonyl,arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent,any of which may be further substituted (e.g., by one or moresubstituents).

The term “alkenyl” refers to a straight or branched hydrocarbon chaincontaining 2-12 carbon atoms (unless otherwise noted) and having one ormore double bonds. Examples of alkenyl groups include, but are notlimited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups.One of the double bond carbons may optionally be the point of attachmentof the alkenyl substituent.

The term “alkenylene” refers to a divalent alkenyl, e.g. —CH═CH—,—CH₂—CH═CH—, and —CH═CH—CH₂—.

The term “alkynyl” refers to a straight or branched hydrocarbon chaincontaining 2-12 carbon atoms (unless otherwise noted) and characterizedin having one or more triple bonds. Examples of alkynyl groups include,but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of thetriple bond carbons may optionally be the point of attachment of thealkynyl substituent.

The term “alkynylene” refers to a divalent alkynyl, e.g. —CH≡CH—,—CH₂—CH≡CH—, and —CH≡CH—CH₂—.

The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group,as defined below, having an oxygen radical attached thereto.Representative alkoxy groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. The term “alkoxyalkyl” refers to an alkyl inwhich one or more hydrogen atoms are replaced by an alkoxy group.

An “ether” is two hydrocarbons covalently linked by an oxygen.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, and branched-chain alkyl groups.In preferred embodiments, a straight chain or branched chain alkyl has12 or fewer carbon atoms in its backbone (unless otherwise noted) e.g.,from 1-12, 1-8, 1-6, or 1-4. Exemplary alkyl moieties include methyl,ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl,isobutyl or t-butyl), pentyl (e.g., n-pentyl, isopentyl or pentan-3-yl),hexyl and hepty.

The term “alkylene” refers to a divalent alkyl, e.g., —CH—, —CH₂ CH₂—,and —CH₂CH₂CH₂—.

The term “alkoxylene” refers to an alkylene wherein a CH₂ is substitutedwith an oxygen. For example, an aryl alkoxylene refers to a group withan alkylene attached to an aryl group through an oxygen, an optionallysubstituted heteroaryl alkoxylene refers to a group with an alkyleneattached to an heteroaryl group through an oxygen.

The term “amino” refers to —NH₂.

The term “aminoalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by an amino group.

The terms “alkylamino” and “dialkylamino” refer to —NH(alkyl) and—N(alkyl)₂ radicals respectively.

The term “aralkylamino” or “arylalkylamino” refers to a —NH(aralkyl)radical. The term “alkylaminoalkyl” refers to a (alkyl)NH-alkyl-radical;the term “dialkylaminoalkyl” refers to an (alkyl)₂N-alkyl-radical.

The term “amido” refers to a —NHC(O)— or C(O)NH₂ substituent.

The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic, or14-carbon tricyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atomsof each ring may be substituted by a substituent. Examples of arylmoieties include, but are not limited to, phenyl, naphthyl and the like.The term “arylalkyl” or “aralkyl” refers to alkyl substituted with anaryl. Exemplary aralkyls include but are not limited to benzyl,1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl,phenethyl, and trityl groups. The term “arylalkenyl” refers to analkenyl substituted with an aryl. The term “arylalkynyl” refers to analkynyl substituted with an aryl. Terms such as “arylC₂-C₆ alkyl” are tobe read as a further limitation on the size of the alkyl group. The term“arylalkoxy” refers to an alkoxy substituted with aryl. The term“arylenyl” refers to a divalent aryl (i.e., —Ar—).

The terms “cycloalkyl” or “cyclyl” as employed herein include saturatedand partially unsaturated cyclic hydrocarbon groups having 3 to 12carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons,wherein the cycloalkyl group may be optionally substituted. Exemplarycyclyl groups include, without limitation, cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl. Cyclyl moieties also include both bridged and fused ringsystems. Cyclyl groups also include those that are fused to additionalring systems, which may be saturated or unsaturated. A cyclyl group maythus be a bicyclic group in which one ring is saturated or partiallyunsaturated and the other is fully unsaturated (e.g., indanyl).

The term “cyclylalkyl” as used herein, refers to an alkyl groupsubstituted with a cyclyl group. Cyclylalkyl includes groups in whichmore than one hydrogen atom of an alkyl group has been replaced by acyclyl group.

The term “cycloalkylalkyl” as used herein, refers to an alkyl groupsubstituted with a cycloalkyl group.

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

The term “haloalkyl” refers to an alkyl group that may have any numberof hydrogens available on the group replaced with a halogen atom.Representative haloalkyl groups include but are not limited to: —CH₂Cl,—CH₂ClCF₃, —CHBr₂, —CF₃, —CH₂F, —CHF₂, and —CH₂CF₃. The term“fluoroalkyl” refers to an alkyl group that may have any number ofhydrogens available on the group replaced with a fluorine atom.Representative fluoroalkyl groups include but are not limited to:—(CH₂F, —CH₂FCF₃, —CHF₂ and —CF₃. The term “haloalkoxy” refers to analkoxy group that may have any number of hydrogen atoms available on thealkyl group replaced with a halogen atom. Representative haloalkoxygroups include but are not limited to: —OCH₂Cl, —OCH₂ClCF₃, —OCHBr₂,—OCHF₂ or —OCF₃. The term “fluoroalkoxy” refers to an alkoxy group thatmay have any number of hydrogens available on the group replaced with afluorine atom, Representative fluoroalkoxy groups include but are notlimited to: —OCH₂F, —OCH₂FCF₃, —OCHF₂ or —OCF₃.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen,sulfur, phosphorus and silicon. A heteroatom may be present in anyoxidation state (e.g., any oxidized form of nitrogen, sulfur, phosphorusor silicon) and any charged state (e.g., the quaternized form of anybasic nitrogen), and includes a substitutable nitrogen of a heterocyclicring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl).

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3,or 4 atoms of each ring may be substituted by a substituent. Examples ofheteroaryl groups include pyridyl, furyl or furanyl, imidazolyl,benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl,thiazolyl, oxazolyl and the like. The term “heteroarylalkyl” or the term“heteroaralkyl” refers to an alkyl substituted with a heteroaryl. Theterm “heteroarylalkenyl” refers to an alkenyl substituted with aheteroaryl. The term “heteroarylalkynyl” refers to an alkynylsubstituted with a heteroaryl. The term “heteroarylalkoxy” refers to analkoxy substituted with heteroaryl.

The term “heteroaryl” refers to a group having 5 to 14 ring atoms,preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π electronsshared in a cyclic array; and having, in addition to carbon atoms, fromone to five heteroatoms. A heteroaryl group may be mono-, bi-, tri-, orpolycyclic, preferably mono-, bi-, or tricyclic, more preferably mono-or bicyclic. When a heteroaryl is substituted by a hydroxy group, italso includes its corresponding tautomer. The term “heteroaryl,” as usedherein, also includes groups in which a heteroaromatic ring is fused toone or more aryl rings. Nonlimiting examples of heteroaryl groupsinclude thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Theterm “heteroaryl” may be used interchangeably with the terms “heteroarylring”, “heteroaryl group,” or “heteroaromatic,” any of which termsinclude rings that are optionally substituted. A ring nitrogen atom of aheteroaryl may be oxidized to form the corresponding N-oxide compound, Anonlimiting example of such a heteroaryl having an oxidized ringnitrogen atom is N-oxopyridyl.

The term “heteroarylalkyl” or “heteroaralkyl” refers to an alkyl groupsubstituted by a heteroaryl. Heteroaralkyl includes groups in which morethan one hydrogen atom has been replaced by a heteroaryl group.

As used herein, the terms “heterocycle,” “heterocyclyl” and“heterocyclic ring” are used interchangeably and refer to a stable 3- to8-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety thatis either saturated or partially unsaturated, and having, in addition tocarbon atoms, one or more, preferably one to four, heteroatoms, asdefined above. When used in reference to a ring atom of a heterocycle,the term “nitrogen” includes a substituted nitrogen. As an example, in asaturated or partially unsaturated ring having 0-3 heteroatoms selectedfrom oxygen, sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2/y-pyrrolyl), NH (as in pyrrolidinyl), or NR⁺ (as inN-substituted pyrrolidinyl). A heterocyclic ring can be attached to itspendant group at any heteroatom or carbon atom that results in a stablestructure and any of the ring atoms can be optionally substituted.Examples of such saturated or partially unsaturated heterocyclicradicals include, without limitation, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl,oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,thiazepinyl, morpholinyl, and thiomorpholinyl. A heterocyclyl group maybe mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic,more preferably mono- or bicyclic. Additionally, a heterocyclic ringalso includes groups in which the heterocyclyl ring is fused to one ormore aryl, heteroaryl or cyclyl rings. A ring nitrogen atom of aheterocyclic ring also may be oxidized to form the correspondingN-hydroxy compound.

The term “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl. Heterocyclylalkyl includes groups in which more than onehydrogen atom has been replaced by a heterocyclyl group.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a heteroaryl group. Exemplary heteroaralkylgroups include but are not limited to methylpyridyl or methylpyrimidyl.

The term “heterocyclyl” or “heterocyclylalkyl” refers to a nonaromatic5-8 membered monocyclic, 5-12 membered bicyclic, or 11-14 memberedtricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6,or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic,respectively), wherein 0, 1, 2 or 3 atoms of each ring may besubstituted by a substituent. Examples of heterocyclyl groups includepiperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, andinclude both bridged and fused ring systems. The term“heterocyclylalkyl” refers to an alkyl substituted with a heterocyclyl.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group.

The term “heteroalkyl,” as used herein, refers to a saturate orunsaturated, straight or branched chain aliphatic group, wherein one ormore of the carbon atoms in the chain are independently replaced by aheteroatom. Exemplary hetero atoms include O, S, and N.

In the case of aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyletc., groups described as optionally substituted, it is intended thateither or both aryl, heteroaryl, cyclyl, heterocyclyl and alkyl moietiesmay be independently optionally substituted or unsubstituted.

The term “hydroxyalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a hydroxy group.

The term “oxo” refers to an oxygen atom (═O), which forms a carbonylwhen attached to carbon, an N-oxide when attached to nitrogen, and asulfoxide or sulfone when attached to sulfur.

The term “thioalkyl” as used herein refers to an —S(alkyl) group, wherethe point of attachment is through the sulfur atom and the alkyl groupis as defined above.

The term “thiono” or “thioxo” refers to a sulfur atom (═S), which formsa thioketone when attached to carbon.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons of the backbone. It will be understoodthat “substitution” or “substituted with” includes the implicit provisothat such substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and non-aromaticsubstituents of organic compounds. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this invention, the heteroatoms such as nitrogen mayhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms.

The term “substituent” refers to a group “substituted” on a moietydescribed herein. Any atom on any substituent can be substituted.Substituents can include any substituents described herein. Exemplarysubstituents include, without limitation, alkyl (e.g., C1, C2, C3, C4,C5, C6, C7, C8, C9, C10, C11, C12 straight or branched chain alkyl),cycloalkyl, haloalkyl (e.g., perfluoroalkyl such as CF₃), aryl,heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl,cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy (e.g.,perfluoroalkoxy such as OCF₃), halo, hydroxy, carboxy, carboxylate,cyano, nitro, amino, alkylamino, SO₃H, sulfate, phosphate,methylenedioxy (—O—CH₂—O— wherein oxygens are attached to vicinalatoms), ethylenedioxy, oxo, thioxo (e.g., C═S), imino (alkyl, aryl,aralkyl), S(O)_(n) alkyl (where n is 0-2), S(O)_(n) aryl (where n is0-2), S(O)_(n) heteroaryl (where n is 0-2), S(O)_(n) heterocyclyl (wheren is 0-2), amine (mono-, di-, alkyl, cycloalkyl, aralkyl, heteroaralkyl,aryl, heteroaryl, and combinations thereof), ester (alkyl, aralkyl,heteroaralkyl, aryl, heteroaryl), amide (mono-, di-, alkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, and combinations thereof), sulfonamide(mono-, di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof).In one aspect, the substituents on a group are independently any onesingle, or any subset of the aforementioned substituents. In anotheraspect, a substituent may itself be substituted with any one of theabove substituents.

As used herein, the phrase “optionally substituted” is usedinterchangeably with the phrase “substituted or unsubstituted.” Ingeneral, the term “substituted”, whether preceded by the term“optionally” or not, means that a hydrogen radical of the designatedmoiety is replaced with the radical of a specified substituent, providedthat the substitution results in a stable or chemically feasiblecompound. The term “substitutable”, when used in reference to adesignated atom, means that attached to the atom is a hydrogen radical,which hydrogen atom can be replaced with the radical of a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a substituent at each substitutable position of thegroup, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds.

As used herein, the term “optionally substituted” means substituted orunsubstituted.

As used herein, the term “partially unsaturated” refers to a moiety thatincludes at least one double or triple bond between atoms. The term“partially unsaturated” encompasses rings, e.g., having one or moresites of unsaturation, but that are not completely unsaturated so as tobe aryl or heteroaryl.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner. With respect to the nomenclature of a chiral center,terms “R” and “S” configuration are as defined by the IUPACRecommendations. The term “enantiomers” refers to two stereoisomers of acompound which are non-superimposable mirror images of one another. Anequimolar mixture of two enantiomers is called a “racemic mixture” or a“racemate.” The term “isomers” or “stereoisomers” refers to compoundswhich have identical chemical constitution, but differ with regard tothe arrangement of the atoms or groups in space. For example, isomersinclude cis- and trans-isomers, E- and Z-isomers, R- and S-enantiomers,diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, andother mixtures thereof. The term “diastereomers” refers to stereoisomerswith two or more centers of dissymmetry and whose molecules are notmirror images of one another.

The term “administration” or “administering” includes routes ofintroducing the compounds, or a composition thereof, of the invention toa subject to perform their intended function. Examples of routes ofadministration that may be used include injection (subcutaneous,intravenous, parenterally, intraperitoneally, intrathecal), oral,inhalation, rectal and transdermal. The pharmaceutical compositions maybe given by forms suitable for each administration route. For example,these compositions are administered in tablets or capsule form, byinjection, inhalation, eye lotion, ointment, suppository, etc.administration by injection, infusion or inhalation; topical by lotionor ointment; and rectal by suppositories. Oral administration ispreferred. The injection can be bolus or can be continuous infusion.Depending on the route of administration, a compound described hereincan be coated with or disposed in a selected material to protect it fromnatural conditions which may detrimentally affect its ability to performits intended function. A compound or composition described herein can beadministered alone, or in conjunction with either another agent asdescribed above or with a pharmaceutically-acceptable carrier, or both.A compound or composition described herein can be administered prior tothe administration of the other agent, simultaneously with the agent, orafter the administration of the agent. Furthermore, a compound describedherein can also be administered in a pro-drug form which is convertedinto its active metabolite, or more active metabolite in vivo.

The language “biological activities” of a compound described hereinincludes all activities elicited by a compound described herein in aresponsive subject or cell. It includes genomic and non-genomicactivities elicited by these compounds.

The terms “inhibit” and “inhibitor” as used herein means an agent thatmeasurably slows or stops the production of STriatal-Enriched tyrosinePhosphatase (STEP), or decreases or inactivates STEP, or interferes withSTEP-mediated biological pathways. Inhibitors of STEP include compoundsof the invention, e.g., compounds of Formulas (I), (II), or (III). Acompound can be evaluated to determine if it is an inhibitor bymeasuring either directly or indirectly the activity of STEP in thepresence of the compound suspected to inhibit STEP. Exemplary methods ofmeasure STEP inhibition are described in the EXAMPLES herein.

An “effective amount” or “an amount effective” refers to an amount ofthe compound or composition which is effective, upon single or multipledose administrations to a subject and for periods of time necessary, intreating a cell, or curing, alleviating, relieving or improving asymptom of a disorder, e.g., a disorder described herein. An effectiveamount of a compound described herein may vary according to factors suchas the disease state, age, and weight of the subject, and the ability ofa compound described herein to elicit a desired response in the subject.Dosage regimens may be adjusted to provide the optimum therapeuticresponse. An effective amount is also one in which any toxic ordetrimental effects (e.g., side effects) of a compound described hereinare outweighed by the therapeutically beneficial effects. The term“effective amount” includes an amount effective, at dosages and forperiods of time necessary, to achieve the desired result, e.g., modulateor regulate protein tyrosine phosphatases, e.g., STEP, in a subjectand/or treat a disorder described herein such as a protein tyrosinephosphatase related disorder. Exemplary disorders include those relatedto cognition, learning and n memory, neurogenesis. An effective amountmay also affect neuronal plasticity, pain perception, mood and anxiety,and neuroendocrine regulation.

An effective amount of a compound described herein may vary according tofactors such as the disease state, age, and weight of the subject, andthe ability of a compound described herein to elicit a desired responsein the subject. Dosage regimens may be adjusted to provide the optimumtherapeutic response. An effective amount is also one in which any toxicor detrimental effects (e.g., side effects) of a compound describedherein are outweighed by the therapeutically beneficial effects.

A therapeutically effective amount of a compound described herein (i.e.,an effective dosage) may range from about 0.001 to 50 mg/kg body weight,preferably about 0.01 to 40 mg/kg body weight, more preferably about 0.1to 35 mg/kg body weight, still more preferably about 1 to 30 mg/kg, andeven more preferably about 10 to 30 mg/kg. The skilled artisan willappreciate that certain factors may influence the dosage required toeffectively treat a subject, including but not limited to the severityof the disease or disorder, previous treatments, the general healthand/or age of the subject, and other diseases present. Moreover,treatment of a subject with a therapeutically effective amount of acompound described herein can include a single treatment or, preferably,can include a series of treatments. In one example, a subject is treatedwith a compound described herein in the range of between about 0.1 to 20mg/kg body weight, one time per week for between about 1 to 10 weeks,preferably between 2 to 8 weeks, more preferably between about 3 to 7weeks, and even more preferably for about 4, 5, or 6 weeks. It will alsobe appreciated that the effective dosage of a compound described hereinused for treatment may increase or decrease over the course of aparticular treatment.

As used herein, an amount of a compound effective to prevent a disorder,or “a prophylactically effective amount” of the compound refers to anamount effective, upon single- or multiple-dose administration to thesubject, in preventing or delaying the occurrence of the onset orrecurrence of a disorder or a symptom of the disorder.

The language “improved biological properties” refers to any activityinherent in a compound described herein that enhances its effectivenessin vivo. In a preferred embodiment, this term refers to any qualitativeor quantitative improved therapeutic property of a compound describedherein, such as reduced off-target effects.

The term “modulate” refers to an increase or decrease, e.g., in theactivity of an enzyme in response to exposure to a compound orcomposition described herein, e.g., the activation or inhibition ofSTEP, in at least a sub-population of cells in a subject such that adesired end result is achieved (e.g., a therapeutic result). In someembodiments, a compound as described herein inhibits a target describedherein, e.g., STEP. In some embodiments, a compound as described hereinis activates a target described herein, e.g., STEP.

As used herein, the term “subject” is intended to include human andnon-human animals. Exemplary human subjects include a human patienthaving a disorder, e.g., a disorder described herein, or a normalsubject. The term “non-human animals” includes all vertebrates, e.g.,non-mammals (such as chickens, amphibians, reptiles) and mammals, suchas non-human primates, domesticated and/or agriculturally usefulanimals, e.g., sheep, dog, cat, cow, pig, etc.

As used herein, the term “treat” or “treating” is defined as applying oradministering a compound or composition, alone or in combination with asecond compound or composition, to a subject, e.g., a patient, orapplying or administering the compound or composition to an isolatedtissue or cell, e.g., cell line, from a subject, e.g., a patient, whohas a disorder (e.g., a disorder as described herein), a symptom of adisorder, or a predisposition toward a disorder, with the purpose tocure, heal, alleviate, relieve, alter, remedy, ameliorate, improve oraffect the disorder, one or more symptoms of the disorder or thepredisposition toward the disorder (e.g., to prevent at least onesymptom of the disorder or to delay onset of at least one symptom of thedisorder).

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The term “prodrug” or “pro-drug” includes compounds with moieties thatcan be metabolized in vivo. Generally, the prodrugs are metabolized invivo by esterases or by other mechanisms to active drugs. Examples ofprodrugs and their uses are well known in the art (See, e.g., Berge etal. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). The prodrugscan be prepared in situ during the final isolation and purification ofthe compounds, or by separately reacting the purified compound in itsfree acid form or hydroxyl with a suitable esterifying agent. Hydroxylgroups can be converted into esters via treatment with a carboxylicacid. Examples of prodrug moieties include substituted andunsubstituted, branch or unbranched lower alkyl ester moieties, (e.g.,propionic acid esters), lower alkenyl esters, di-lower alkyl-aminolower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino loweralkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters(e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-loweralkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo,or methoxy substituents) aryl and aryl-lower alkyl esters, amides,lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferredprodrug moieties are propionic acid esters and acyl esters. Prodrugswhich are converted to active forms through other mechanisms in vivo arealso included.

The language “a prophylactically effective amount” of a compound refersto an amount of a compound described herein any formula herein orotherwise described herein which is effective, upon single or multipledose administration to the patient, in preventing or treating a diseaseor condition.

The language “reduced off-target effects” is intended to include areduction in any undesired side effect elicited by a compound describedherein when administered in vivo. In some embodiments, a compounddescribed herein has little to no cardio and/or pulmonary toxicity(e.g., when administered to a subject). In some embodiments, a compounddescribed herein has little to no hallucinogenic activity (e.g., whenadministered to a subject).

The term “selective” means a greater activity against a first target. Insome embodiments a compound has a selectivity of at least 1.25-fold, atleast 1.5 fold, at least 2-fold, at least 3-fold, at least 4-fold, atleast 5-fold, at least 6-fold, at least 10-fold or at least 100-foldgreater towards a first target relative to a second target. In someembodiments, a compound described herein, e.g., a compound of Formulas(I), (II), or (III) is selective toward STEP relative to one or moreother protein tyrosine phosphatases.

The term “subject” includes organisms which are capable of sufferingfrom a serotonin-receptor-related disorder or who could otherwisebenefit from the administration of a compound described herein of theinvention, such as human and non-human animals. Preferred humans includehuman patients suffering from or prone to suffering from aserotonin-related disorder or associated state, as described herein. Theterm “non-human animals” of the invention includes all vertebrates,e.g., mammals, e.g., rodents, e.g., mice, and non-mammals, such asnon-human primates, e.g., sheep, dog, cow, chickens, amphibians,reptiles, etc.

The phrases “systemic administration,” “administered systemically”,“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound described herein(s), drugor other material, such that it enters the patient's system and, thus,is subject to metabolism and other like processes, for example,subcutaneous administration.

Compounds

The compounds described herein can be used for a variety of purposes,e.g., therapeutic purposes. Many of the compounds modulate STEP activityand can be used, for example to inhibit STEP, e.g., in a subject.

Exemplary compounds include a compound of formula (I):

wherein A, B, E, L, X, Z, R¹, R², R³, m, n and p are as defined above inthe section relating to compound of Formula (I). In preferredembodiments, L is NH, B is aryl (e.g., phenyl) that may be optionallysubstituted, E is aryl (e.g., phenyl), A is N, X is CH and Z is N.

Exemplary compounds include a compound of formula (II):

wherein A, L, X¹, X², X³, X⁴, X⁵, R¹, R², R³, n and p are as definedabove in the section relating to compound of Formula (II).

Exemplary compounds include a compound of formula (III):

wherein A, L, X¹, X², X³, X⁴, X⁵, R¹, R², R³, R⁴, m and n are as definedabove in the section relating to compound of Formula (III).

Exemplary compounds include a compound of formula (IV):

wherein A, B, E, L, X, Z, R¹, R², R³, m, n and p are as defined above inthe section relating to compound of Formula (IV). In preferredembodiments, L is NH, B is aryl (e.g., phenyl) that may be optionallysubstituted, E is aryl (e.g., phenyl), A is N, X is CH and Z is N.

Exemplary compounds include a compound of formula (V):

wherein A, L, X¹, X², X³, X⁴, X⁵, R¹, R², R³, n and p are as definedabove in the section relating to compound of Formula (V).

Exemplary compounds include a compound of formula (VI):

wherein A, L, X¹, X², X³, X⁴, R¹, R², R³, R⁴, m, and n are as definedabove in the section relating to compound of Formula (VI).

The present invention includes compounds that differ only in thepresence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, the replacement of a carbon by a ¹³C-or ¹⁴C-enriched carbon, or the replacement of a fluorine by a¹⁹F-enriched fluorine are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays, or as bioactive agents.

In the compounds of the present invention, any atom not specificallydesignated as a particular isotope is meant to represent any stableisotope of that atom unless otherwise stated (e.g., hydrogen, ²H ordeuterium and ³H or tritium). The formulas described herein may or maynot indicate whether atoms at certain positions are isotopicallyenriched. When a structural formula is silent with respect to whether aparticular position is isotopically enriched, it is to be understoodthat the isotopes at that particular position are present in naturalabundance or, that the particular position is isotopically enriched withone or more naturally occurring stable isotopes. For example, theformula —CH₂— represents the following possible structures: —CH₂—, —CHD-or —CD₂-.

The variable “D” is defined as deuterium.

The terms “compound” or “compounds,” when referring to a compound ofthis invention or a compound described herein, refers to a collection ofmolecules having an identical chemical structure, except that there maybe isotopic variation among the constituent atoms of the molecules.Thus, it will be clear to those of skill in the art that a compoundrepresented by a particular chemical structure containing indicatedhydrogen atoms will contain lesser amounts of isotopologues havingdeuterium atoms at one or more of the designated hydrogen positions inthat structure. Alternatively, a compound represented by a particularchemical structure containing indicated deuterium atoms will containlesser amounts of isotopologues having hydrogen atoms at one or more ofthe designated deuterium positions in that structure. The relativeamount of such isotopologues in a compound of this invention will dependon a number of factors including isotopic purity of deuterated reagentsused to make the compound and the efficiency of incorporation ofdeuterium in the various synthetic steps used to prepare the compound.The relative amount of such isotopologues in total will be less than 55%of the compound. In other embodiments, the relative amount of suchisotopologues in total will be less than 50%, less than 45%, less than40%, less than 35%, less than 35%, less than 15%, less than 10%, lessthan 5%, less than 1% or less than 0.5% of the compound.

The term “isotopologue” refers to a species that differs from a specificcompound of this invention only in the isotopic composition thereof.Isotopologues can differ in the level of isotopic enrichment at one ormore positions and/or in the position(s) of isotopic enrichment.

The compounds of this invention may contain one or more asymmetriccenters and thus occur as racemates and racemic mixtures, singleenantiomers, individual diastereomers and diastereomeric mixtures.Described herein are enantiomerically enriched compounds (e.g., acompound resolved to an enantiomeric excess of 60%, 70%, 80%, 85%, 90%,95%, 99% or greater). All such isomeric forms of these compounds areexpressly included in the present invention. The compounds of thisinvention may also contain linkages (e.g., carbon-carbon bonds) orsubstituents that can restrict bond rotation, e.g. restriction resultingfrom the presence of a ring or double bond. Accordingly, all cis/transand E/Z isomers are expressly included in the present invention. Thecompounds of this invention may also be represented in multipletautomeric forms, in such instances, the invention expressly includesall tautomeric forms of the compounds described herein, even though onlya single tautomeric form may be represented (e.g., alkylation of a ringsystem may result in alkylation at multiple sites, the inventionexpressly includes all such reaction products). All such isomeric formsof such compounds are expressly included in the present invention. Allcrystal forms of the compounds described herein are expressly includedin the present invention.

Naturally occurring or synthetic isomers can be separated in severalways known in the art. Methods for separating a racemic mixture of twoenantiomers include chromatography using a chiral stationary phase (see,e.g., “Chiral Liquid Chromatography,” W. J. Lough, Ed. Chapman and Hall,New York (1989)). Enantiomers can also be separated by classicalresolution techniques. For example, formation of diastereomeric saltsand fractional crystallization can be used to separate enantiomers. Forthe separation of enantiomers of carboxylic acids, the diastereomericsalts can be formed by addition of enantiomerically pure chiral basessuch as brucine, quinine, ephedrine, strychnine, and the like.Alternatively, diastereomeric esters can be formed with enantiomericallypure chiral alcohols such as menthol, followed by separation of thediastereomeric esters and hydrolysis to yield the free, enantiomericallyenriched carboxylic acid. For separation of the optical isomers of aminocompounds, addition of chiral carboxylic or sulfonic acids, such ascamphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid canresult in formation of the diastereomeric salts. For example a compoundcan be resolved to an enantiomeric excess (e.g., 60%, 70%, 80%, 85%,90%, 95%, 99% or greater) via formation of diasteromeric salts, e.g.with a chiral base, e.g., (+) or (−) α-methylbenzylamine, or via highperformance liquid chromatography using a chiral column. In someembodiments a product is purified directly on a chiral column to provideenantiomerically enriched compound.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic administration to asubject).

Compounds of formulas (I), (II), (Iii), (IV), (V), and (VI) aredescribed herein, for example as provided in the summary above.Exemplary compounds are shown in Tables 1-30 in the Examples section.

Synthetic Methods

A compound described herein may be prepared via a variety of syntheticmethods. Representative syntheses are shown in the Examples section.

As can be appreciated by the skilled artisan, further methods ofsynthesizing the compounds of the formulae herein will be evident tothose of ordinary skill in the art. Additionally, the various syntheticsteps may be performed in an alternate sequence or order to give thedesired compounds. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe compounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

Additionally, the compounds disclosed herein can be prepared on a solidsupport. The term “solid support” refers a material to which a compoundis attached to facilitate identification, isolation, purification, orchemical reaction selectivity of the compound. Such materials are knownin the art and include, for example, beads, pellets, disks, fibers,gels, or particles such as cellulose beads, pore-glass beads, silicagels, polystyrene beads optionally cross-linked with divinylbenzene andoptionally grafted with polyethylene glycol, poly-acrylamide beads,latex beads, dimethylacrylamide beads optionally cross-linked withN,N′-bis-acryloyl ethylene diamine, glass particles coated withhydrophobic polymer, and material having a rigid or semi-rigid surface.The solid supports optionally have functional groups such as amino,hydroxy, carboxy, or halo groups, (see, Obrecht, D. and Villalgrodo, J.M., Solid-Supported Combinatorial and Parallel Synthesis ofSmall-Molecular-Weight Compound Libraries, Pergamon-Elsevier ScienceLimited (1998)), and include those useful in techniques such as the“split and pool” or “parallel” synthesis techniques, solid-phase andsolution-phase techniques, and encoding techniques (see, for example,Czarnik, A. W., Curr. Opin. Chem. Bio., (1997) 1, 60).

A compound described herein may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., brain,blood, lymphatic system, central nervous system), increase oralavailability, increase solubility to allow administration by injection,alter metabolism and alter rate of excretion.

Included herein are pharmaceutically acceptable derivatives or prodrugsof the compounds described herein. A “pharmaceutically acceptablederivative or prodrug” means any pharmaceutically acceptable salt,ester, salt of an ester, or other derivative of a compound of thisinvention (for example an imidate ester of an amide), which, uponadministration to a recipient, is capable of providing (directly orindirectly) a compound described herein. Particularly favoredderivatives and prodrugs are those that increase the bioavailability ofthe compounds of this invention when such compounds are administered toa mammal (e.g., by allowing an orally administered compound to be morereadily absorbed into the blood) or which enhance delivery of the parentcompound to a biological compartment (e.g., the brain or lymphaticsystem) relative to the parent species. In an exemplary embodiment, theprodrug is a derivative including a group that enhances aqueoussolubility or active transport through the gut membrane is appended tothe structure of formulae described herein. In another exemplaryembodiment, the prodrug is suitable for treatment or prevention of thosediseases and conditions that require the drug molecule to cross theblood brain barrier. In a preferred embodiment, the prodrug enters thebrain, where it is converted into the active form of the drug molecule.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acid salts includeacetate, adipate, benzoate, benzenesulfonate, butyrate, citrate,digluconate, dodecylsulfate, formate, fumarate, glycolate, hemisulfate,heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, palmoate, phosphate, picrate, pivalate, propionate,salicylate, succinate, sulfate, tartrate, tosylate and undecanoate.Salts derived from appropriate bases include alkali metal (e.g.,sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl)₄⁺ salts. This invention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Water oroil-soluble or dispersible products may be obtained by suchquaternization.

Evaluating Compounds

A variety of methods can be used to evaluate a compound for ability tomodulate STEP activity. Evaluation methods include in vitro assays(e.g., enzyme-based assays), in vitro cell-based signaling assays, andin vivo methods (e.g., testing in animal models). The evaluation methodscan evaluate binding activity, phosphatase activity, or an activitydownstream of STEP, such as the activity of ERK.

For example, a compound described herein may be evaluated using afluorescence-based phosphatase assay. A phosphate-containing reagent maybe used in the assay which, upon dephosphorylation by a phosphatase,generates a fluorescent product that may be detected using a fluorometeror fluorescence plate reader. Data may be expressed as percentage (%)inhibition of enzyme activity. For compounds showing enzymaticactivation, data may be represented as percentage of inhibition but withnegative values.

Compositions and Routes of Administration

The invention also provides a pharmaceutical composition, comprising aneffective amount of a compound described herein (e.g., a compoundcapable of treating or preventing a condition as described herein, e.g.,a compound of any formula herein or otherwise described herein) and apharmaceutically acceptable carrier.

The compositions delineated herein include the compounds delineatedherein (e.g., a compound described herein), as well as additionaltherapeutic agents if present, in amounts effective for achieving amodulation of disease or disease symptoms, including those describedherein.

The term “pharmaceutically acceptable carrier or adjuvant” refers to acarrier or adjuvant that may be administered to a patient, together witha compound of this invention, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-α-tocopherol polyethylene glycol 1000 succinate, surfactants used inpharmaceutical dosage forms such as Tweens or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, or carboxymethyl cellulose or similar dispersing agentswhich are commonly used in the formulation of pharmaceuticallyacceptable dosage forms such as emulsions and or suspensions. Othercommonly used surfactants such as Tweens or Spans and/or other similaremulsifying agents or bioavailability enhancers which are commonly usedin the manufacture of pharmaceutically acceptable solid, liquid, orother dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions. In the case of tablets for oral use, carrierswhich are commonly used include lactose and corn starch, Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions and/or emulsions areadministered orally, the active ingredient may be suspended or dissolvedin an oily phase is combined with emulsifying and/or suspending agents.If desired, certain sweetening and/or flavoring and/or coloring agentsmay be added.

The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax and polyethyleneglycols.

Topical administration of the pharmaceutical compositions of thisinvention is useful when the desired treatment involves areas or organsreadily accessible by topical application. For application topically tothe skin, the pharmaceutical composition should be formulated with asuitable ointment containing the active components suspended ordissolved in a carrier. Carriers for topical administration of thecompounds of this invention include, but are not limited to, mineraloil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier with suitable emulsifying agents. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water. The pharmaceuticalcompositions of this invention may also be topically applied to thelower intestinal tract by rectal suppository formulation or in asuitable enema formulation. Topically-transdermal patches are alsoincluded in this invention.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

When the compositions of this invention comprise a combination of acompound of the formulae described herein and one or more additionaltherapeutic agents, both the compound and the additional agent should bepresent at dosage levels of between about 1 to 100%, and more preferablybetween about 5 to 95% of the dosage normally administered in amonotherapy regimen. The additional agents may be administeredseparately, as part of a multiple dose regimen, from the compounds ofthis invention. Alternatively, those agents may be part of a singledosage form, mixed together with the compounds of this invention in asingle composition.

The compounds described herein can, for example, be administered byinjection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.5 toabout 100 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. A typical preparation will contain from about 5%to about 95% active compound (w/w). Alternatively, such preparationscontain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

Methods of Treatment

The compounds and compositions described herein can be administered tocells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., invivo, to treat, prevent, and/or diagnose a variety of disorders,including those described herein below.

The compounds and compositions described herein can be administered to asubject, for example using a method described herein, who is sufferingfrom a disorder described herein, e.g., a disorder that would benefitfrom the modulation of STEP (e.g., activating or inhibiting STEP). Thecompounds and compositions described herein can be administered to asubject, for example using a method described herein, who is at risk fora disorder described herein, e.g., a disorder that would benefit fromthe modulation of STEP (e.g., activating or inhibiting STEP).

Inhibitors of STEP may increase phosphorylation of an NMDA-R. Thus, insome embodiments, a compound described herein, e.g., a compound thatinhibits STEP, may be useful for treating a disorder in which increasingphosphorylation of an NMDA-R would be beneficial.

Inhibitors of STEP may activate an ERK1 or ERK2 kinase, for example, inthe CNS. Thus, in some embodiments, a compound described herein, e.g., acompound that inhibits STEP, may be useful for treating a disorder inwhich activate an ERK1 or ERK2 kinase would be beneficial.

Compounds described herein may be useful in treating a variety ofdisorders, including disorders of the CNS. Exemplary disorders includeschizophrenia, schizo-affective disorders, major depression, bipolardisorder, cognitive deficit, mild cognitive impairment (MCI),Alzheimer's disease (AD), attention-deficit/hyperactivity disorder(ADHD), dementia, generalized anxiety disorders, panic disorders,obsessive-compulsive disorders, phobias, post-traumatic stress syndrome,anorexia nervosa, drug addiction, ischemic stroke, head trauma or braininjury, Huntington's disease, Parkinson's disease, spinocerebellardegeneration, motor neuron diseases, epilepsy, neuropathic pain, chronicpain, neuropathies, autism and autistic disorders.

Compounds described herein may be useful for treating or preventingcentral nervous system disorders selected from the group consisting ofschizophrenia; refractory, intractable or chronic schizophrenia;emotional disturbance; psychotic disorder; mood disorder; bipolar I typedisorder; bipolar II type disorder; depression; endogenous depression;major depression; melancholy and refractory depression; dysthymicdisorder; cyclothymic disorder; panic attack; panic disorder;agoraphobia; social phobia; obsessive-compulsive disorder;post-traumatic stress disorder; generalized anxiety disorder; acutestress disorder; hysteria; somatization disorder; conversion disorder;pain disorder; hypochondriasis; factitious disorder; dissociativedisorder; sexual dysfunction; sexual desire disorder; sexual arousaldisorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleepdisorder; adjustment disorder; alcohol abuse; alcohol intoxication; drugaddiction; stimulant intoxication; narcotism; anhedonia; iatrogenicanhedonia; anhedonia of a psychic or mental cause; anhedonia associatedwith depression; anhedonia associated with schizophrenia; delirium;cognitive impairment; cognitive impairment associated with Alzheimer'sdisease, Parkinson's disease and other neurodegenerative diseases;cognitive impairment caused by Alzheimer's disease; Parkinson's diseaseand associated neurodegenerative diseases; cognitive impairment ofschizophrenia; cognitive impairment caused by refractory, intractable orchronic schizophrenia; vomiting; motion sickness; obesity; migraine;pain (ache); mental retardation; autism disorder (autism); Tourette'sdisorder; tic disorder; attention-deficit/hyperactivity disorder;conduct disorder; and Down's syndrome.

Compounds described herein may be useful for treating or preventingdisorders selected from schizophrenia, schizoaffective disorder, bipolardisorder, manic-depressive disorder, psychosis, mood and anxietydisorders, mania, drug or substance addiction, cognition disorders,learning disabilities, learning and memory disorders, aging andneurologic disorders associated with or linked with cognitiveimpairments; mild cognitive impairments (MCI), Alzheimer's disease,Alzheimer-related cognition disorders, Huntington's disease, Parkinson'sdisease, CADASIL syndrome (cerebral autosomal dominant arteriopathy withsubcortical infarcts and leukoencephalopathy), amnesia,Wernicke-Korsakoff syndrome, Korsakoff syndrome, mild traumatic headinjury (MBTI), traumatic head injury (TBI), fragile X syndrome, stroke,attention-deficit and hyperactivity disorder (ADHD), obsessivecompulsive disorder (OCD), post-traumatic stress disorder (PTSD), lossof concentration, autism, cerebral palsy, encephalopathy, andnarcolepsy. The disorder may affect learning and memory, neurogenesis,neuronal plasticity, pain perception, mood and anxiety, orneuroendocrine regulation. The disorder may be a cognitive deficitdisorder. The disorder may involve pain perception or neuroendocrineregulation.

Schizophrenia

In some embodiments, a compound or composition described herein can beused in the treatment of schizophrenia. Schizophrenia is a psychiatricdiagnosis that describes a mental disorder characterized byabnormalities in the perception or expression of reality. Distortions inperception may affect all five senses, including sight, hearing, taste,smell and touch, but most commonly manifests as auditory hallucinations,paranoid or bizarre delusions, or disorganized speech and thinking withsignificant social or occupational dysfunction. Onset of symptomstypically occurs in young adulthood, with approximately 0.4-0.6% of thepopulation affected. Diagnosis is based on the patient's self-reportedexperiences and observed behavior.

The disorder is thought to mainly affect cognition, but it also usuallycontributes to chronic problems with behavior and emotion. People withschizophrenia are likely to have additional (comorbid) conditions,including major depression and anxiety disorders. Social problems, suchas long-term unemployment, poverty and homelessness, are common.Furthermore, the average life expectancy of people with the disorder is10 to 12 years less than those without, due to increased physical healthproblems and a higher suicide rate.

The Diagnostic and Statistical Manual of Mental Disorders (DSM) containsfive sub-classifications of schizophrenia. These include Paranoid type(where delusions and hallucinations are present but thought disorder,disorganized behavior, and affective flattening are absent);Disorganized type (also known as hebephrenic schizophrenia, wherethought disorder and flat affect are present together); Catatonic type(the subject may be almost immobile or exhibit agitated, purposelessmovement; symptoms can include catatonic stupor and waxy flexibility);Undifferentiated type (psychotic symptoms are present but the criteriafor paranoid, disorganized, or catatonic types have not been met); andResidual type (where positive symptoms are present at a low intensityonly).

The International Statistical Classification of Diseases and RelatedHealth Problems (10th Revision) defines two additional subtypes. Theseinclude Post-schizophrenic depression (a depressive episode arising inthe aftermath of a schizophrenic illness where some low-levelschizophrenic symptoms may still be present); and Simple schizophrenia(insidious and progressive development of prominent negative symptomswith no history of psychotic episodes.)

An agent for the treatment of schizophrenia may improve so-calledpositive symptoms in the acute period of schizophrenia such ashallucinations, delusions, excitations and the like. An agent fortreating schizophrenia may also improve so-called negative symptoms thatare observed in the chronic period of schizophrenia such as apathy,emotional depression, hyposychosis and the like.

Schizoaffective Disorder

Schizoaffective disorder is a psychiatric diagnosis that describes amental disorder characterized by recurring episodes of elevated ordepressed mood, or simultaneously elevated and depressed mood thatalternate or occur together with distortions in perception. Theperceptual distortion component of the disorder, called psychosis, mayaffect all five senses, including sight, hearing, taste, smell andtouch, but most commonly manifest as auditory hallucinations, paranoidor bizarre delusions, or disorganized speech and thinking withsignificant social and occupational dysfunction. The elevated, depressedor simultaneously elevated and depressed mood episode components of thedisorder, called mood disorder, are broadly recognized as depressive andbipolar types of the illness; the division is based on whether theindividual has ever had a manic, hypomanic or mixed episode. Onset ofsymptoms usually begins in early adulthood and is rarely diagnosed inchildhood (prior to age 13). The lifetime prevalence of the disorder isuncertain (due to studies using varying diagnostic criteria), althoughit is generally agreed to be less than 1 percent, and possibly in therange of 0.5 to 0.8 percent. Diagnosis is based on the patient'sself-reported experiences and observed behavior. No laboratory test forschizoaffective disorder currently exists. As a group, people withschizoaffective disorder have a more favorable prognosis than peoplewith schizophrenia, but a worse prognosis than those with mooddisorders.

The disorder is thought to mainly affect cognition and emotion, but italso usually contributes to ongoing problems with behavior andmotivation. People with schizoaffective disorder are likely to haveadditional (comorbid) conditions, including anxiety disorders andsubstance abuse. Social problems, such as long-term unemployment,poverty and homelessness, are common. Furthermore, the average lifeexpectancy of people with the disorder is shorter than those without thedisorder, due to increased physical health problems and a higher suiciderate.

Cognitive Deficit

Treatment using a compound or composition described herein may improve acognitive deficit associated with a cognition-related disorder.Cognitive deficit is an inclusive term to describe any characteristicthat acts as a barrier to cognitive performance. The term may describedeficits in global intellectual performance, such as mental retardation,it may describe specific deficits in cognitive abilities (learningdisorders, dyslexia), or it may describe drug-induced cognitive/memoryimpairment, such as that seen with alcohol and the benzodiazepines.Cognitive deficits may be congenital or caused by environmental factorssuch as brain injuries, neurological disorders, or mental illness.

Exemplary cognition-related disorders (e.g., cognitive dysfunction)include, without limitation, mild cognitive impairment (MCI), dementia,delirium, amnestic disorder, Alzheimer's disease, Parkinson's diseaseand Huntington's disease; memory disorders including memory deficitsassociated with depression, senile dementia, dementia of Alzheimer'sdisease; cognitive deficits or cognitive dysfunction associated withneurological conditions including, for example, Parkinson's disease(PD), Huntington's disease (HD), Alzheimer's disease, depression,schizophrenia and other psychotic disorders such as paranoia andmanic-depressive illness; cognitive dysfunction in schizophrenia:disorders of attention and learning such as attention deficit disorders(e.g., attention deficit hyperactivity disorder (ADHD)) and dyslexia;cognitive dysfunction associated with developmental disorders such asDown's syndrome and Fragile X syndrome; loss of executive function: lossof learned information; vascular dementia; schizophrenia; cognitivedecline; a neurodegenerative disorder; and other dementias, for example,dementia due to HIV disease, head trauma, Parkinson's disease,Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or dueto multiple etiologies. Cognition-related disorders also include,without limitation, cognitive dysfunction associated with MCI anddementias such as Lewy Body, vascular, and post stroke dementias.Cognitive dysfunction associated with surgical procedures, traumaticbrain injury or stroke may also be treated in accordance with theembodiments described herein.

Major Depression

Major depression (also known as clinical depression, major depressivedisorder, unipolar depression, or unipolar disorder) is a mentaldisorder characterized by a pervasive low mood, low self-esteem, andloss of interest or pleasure in normally enjoyable activities. Types ofMajor depressive disorder include, e.g., Atypical depression,Melancholic depression, Psychotic depression, Catatonic depression,Postpartum depression, and Seasonal affective disorder.

Bipolar Disorder

Bipolar disorder, also known as manic depressive disorder, manicdepressive psychosis, manic depression or bipolar affective disorder, isa psychiatric diagnosis that describes a category of mood disordersdefined by the presence of one or more episodes of abnormally elevatedmood clinically referred to as mania or, if milder, hypomania.Individuals who experience manic episodes also commonly experiencedepressive episodes or symptoms, or mixed episodes in which features ofboth mania and depression are present at the same time. These episodesare usually separated by periods of “normal” mood, but in someindividuals, depression and mania may rapidly alternate, known as rapidcycling. Extreme manic episodes can sometimes lead to psychotic symptomssuch as delusions and hallucinations. The disorder has been subdividedinto bipolar I, bipolar II, cyclothymia, and other types, based on thenature and severity of mood episodes experienced; the range is oftendescribed as the bipolar spectrum.

Anxiety Disorders

Anxiety disorder is a blanket term covering several different forms ofabnormal and pathological fear and anxiety. Current psychiatricdiagnostic criteria recognize a wide variety of anxiety disorders.Recent surveys have found that as many as 18% of Americans may beaffected by one or more of them.

Generalized anxiety disorder is a common chronic disorder characterizedby long-lasting anxiety that is not focused on any one object orsituation. Those suffering from generalized anxiety experiencenon-specific persistent fear and worry and become overly concerned witheveryday matters. Generalized anxiety disorder is the most commonanxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terrorand apprehension, often marked by trembling, shaking, confusion,dizziness, nausea, difficulty breathing. These panic attacks, defined bythe APA as fear or discomfort that abruptly arises and peaks in lessthan ten minutes, can last for several hours and can be triggered bystress, fear, or even exercise; although the specific cause is notalways apparent. In addition to recurrent unexpected panic attacks, adiagnosis of panic disorder also requires that said attacks have chronicconsequences: either worry over the attacks' potential implications,persistent fear of future attacks, or significant changes in behaviorrelated to the attacks. Accordingly, those suffering from panic disorderexperience symptoms even outside of specific panic episodes. Often,normal changes in heartbeat are noticed by a panic sufferer, leadingthem to think something is wrong with their heart or they are about tohave another panic attack. In some cases, a heightened awareness(hypervigilance) of body functioning occurs during panic attacks,wherein any perceived physiological change is interpreted as a possiblelife threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarilycharacterized by repetitive obsessions (distressing, persistent, andintrusive thoughts or images) and compulsions (urges to perform specificacts or rituals). The OCD thought pattern may be likened tosuperstitions insofar as it involves a belief in a causativerelationship where, in reality, one does not exist. Often the process isentirely illogical; for example, the compulsion of walking in a certainpattern may be employed to alleviate the obsession of impending harm.And in many cases, the compulsion is entirely inexplicable, simply anurge to complete a ritual triggered by nervousness. In a minority ofcases, sufferers of OCD may only experience obsessions, with no overtcompulsions; a much smaller number of sufferers experience onlycompulsions.

The single largest category of anxiety disorders is that of Phobia,which includes all cases in which fear and anxiety is triggered by aspecific stimulus or situation. Sufferers typically anticipateterrifying consequences from encountering the object of their fear,which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder whichresults from a traumatic experience. Post-traumatic stress can resultfrom an extreme situation, such as combat, rape, hostage situations, oreven serious accident. It can also result from long term (chronic)exposure to a severe stressor, for example soldiers who endureindividual battles but cannot cope with continuous combat. Commonsymptoms include flashbacks, avoidant behaviors, and depression.

Combination Therapies

In some embodiments, the subject is being treated with an additionaltherapeutic agent. Such additional agents include atypicalantipsychotics such as aripiprazole, clozapine, ziprasidone,risperidone, quetiapine, olanzapine, amisulpride, asenapine,iloperidone, melperone, paliperidone, perospirone, sertindole andsulpiride; and typical antipsychotics such as haloperidol, molindone,loxapine, thioridazine, molindone, thiothixene, pimozide, fluphenazine,trifluoperazine, mesoridazine, chlorprothixene, chlorpromazine,perphenazine, triflupromazine and zuclopenthixol.

Clinical Outcomes

In some embodiments, treatment with a compound or composition describedherein, for example, using a method described herein, improves one ormore clinical outcomes. For example, in some embodiments, treatment witha compound or composition described herein may improve cognitivefunction. Elements of cognitive function include memory, orientation,attention, reasoning, language and praxis.

In some embodiments, clinical outcomes may be assessed using knownmethods. One such method is the Brief Psychiatric Rating Scale (BPRS), amulti-item inventory of general psychopathology traditionally used toevaluate the effects of drug treatment in schizophrenia. The BPRSpsychosis cluster (conceptual disorganization, hallucinatory behavior,suspiciousness, and unusual thought content) is considered aparticularly useful subset for assessing actively psychoticschizophrenic patients.

In some embodiments, clinical outcomes may be assessed using the 7-pointClinical Global Impression (CGI) rating scale, a commonly used measureof symptom severity, treatment response and the efficacy of treatments.The CGI reflects the impression of a skilled observer, fully familiarwith the manifestations of schizophrenia, about the overall clinicalstate of the patient.

In some embodiments, clinical outcomes may be assessed using the 30-itemPositive and Negative Symptoms Scale (PANSS). The name refers to the twotypes of symptoms in schizophrenia, as defined by the AmericanPsychiatric Association: positive symptoms, which refer to an excess ordistortion of normal functions (e.g. hallucinations and delusions), andnegative symptoms, which represent a dimunition or loss of normalfunctions.

In some embodiments, clinical outcomes may be assessed using the Scalefor Assessing Negative Symptoms (SANS). SANS assesses five symptomcomplexes to obtain clinical ratings of negative symptoms in patientswith schizophrenia. They are: affective blunting; alogia (impoverishedthinking); avolition/apathy; anhedonia/asociality; and disturbance ofattention. Assessments are conducted on a six-point scale.

The invention is further illustrated by the following examples which areintended to illustrate but not limit the scope of the invention.

EXAMPLES Abbreviations

DCM: Dichloromethane

EA, EtOAc or AcOEt: Ethyl acetate

PE: Petroleum ether

DIPEA: Diisopropylethylamine

TEA: Triethyl amine

rt: Room temperature

SOCl₂: Thionyl chloride

POCl₃: Phosphorous oxychloride

TH: Tetrahydrofuran

NaOAc: Sodium acetate

MeOH: Methanol

i-AmOH: Isoamyl alcohol

NaH: Sodium hydride

NaBH₃CN: Sodium cyanoborohydride

n-BuLi: n-Butyl lithium

LHMDS: Lithium bis(trimethylsilyl)amide

LDA: Lithium diisopropylamide

i-PrOH: Isopropyl alcohol

Na₂SO₄: Sodium sulfate

Mg₂SO₄: Magnesium sulfate

MeCN: Acetonitrile

NaOH: Sodium hydroxide

EtOH: Ethanol

CuI: Copper(I) iodide

Pd(PPh₃)₂Cl₂: trans-Dichlorobis(triphenylphosphine)palladium(II)

MsCl: Methanesulfonyl chloride

BINAM: [1,1′-Binaphthalene]-2,2′-diamine

Xphos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Sphos: 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl

DavePhos: 2-(Dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl

Cs₂CO₃: Cesium carbonate

K₂CO₃: Potassium carbonate

Mwave or μW or mW: Microwave

t-BuOH: tert-Butanol

K₃PO₄: Potassium phosphate

Pd(APhos)₂Cl₂:Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)

Pd(PPh₃)₄: Tetrakis(triphenylphosphine)palladium (0)

Pd(dppf)₂Cl₂:Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)

PdOAc: Palladium(II) acetate

Pd₂dba₃: Tris(dibenzylideneacetone)dipalladium (0)

Pd-118: Dichloro[1,1-bis(di-1-butylphosphino)ferrocene]palladium(II)

Xantphos: 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene

BINAP: (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene

EDCI: 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide

HOBt: Hydroxybenzotriazole

NH₄OH: Ammonium hydroxide

H₂O: Water

Pd/C: Palladium on carbon

DMF: N,N-Dimethylformamide

KOCN: Potassium cyanate

WSC-HCl or WSCDI: Water Soluble Carbodiimide hydrochloride

HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

HBTU: O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

Py-Brop: Bromotripyrrolidinophosphonium hexafluorophosphate

BOP: Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate

DBU: diaza(1,3)bicyclo[5.4.0]undecene

DMSO: Dimethyl sulfoxide

LCMS: Liquid chromatography mass spectrometry

HPLC: High performance liquid chromatography

DMA: N,N-dimethylacetamide

h: hour

TLC: Thin layer chromatography

TFA: Trifluoroacetic acid

Et₃N: Triethylamine

DIPEA: N,N-Diisopropylethylamine

O.N: Overnight

TBSO: tert-Butyldimethylsilyloxy

DME: Dimethyl ether

NMP: 1-methyl-2-pyrrolidinone

PS-BEMP:2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorinesupported on Polystyrene

PBr₃: Phosphorus tribromide

NaOtBu: Sodium tert-butoxide

KI: Potassium iodide

PPh₃: Triphenylphosphine

NMM: N-Methylmorpholine

HCHO: Formaldehyde

PG: Protecting group

ISCO: Teledyne ISCO purification systems

BINAM: 1,1′-binaphthyl-2,2′-diamine.

General Experimental

All exemplified target compounds are fully analyzed and characterized(TLC, LCMS, ¹H-NMR) prior to submission for biological evaluation.Thin-layer chromatography was carried out on native silica 254F plates.Visualization was accomplished with ultraviolet or phosphomolybdic acid.¹H-NMR spectra were recorded on multiple NMR spectrometers, either on400 MHz on a Avance III 1400 Ultra shield-plus TM digital Spectrometeror on 300 MHz using a Varian Mercury 300Plus Spectrometer, designated by400 MHz or 300 MHz, respectively. ¹H-NMR spectra were also recorded on aBruker Spectrospin 300 MHz Spectrometer at 300.13 MHz in DMSO-d6 withTMS as an internal standard and will be designated as Bruker 300 Hz. NMRassignments are based on a combination of the ¹H, ¹³C, ¹HCOSY, HMBC andHMQC spectra. Coupling constants are given in hertz (Hz). Anhydrousmethylene chloride, tetrahydrofuran, and dimethylformamide were obtainedby distillation, and other materials are reagent grade.

LC-MS Methods are listed here:

Method A: Mobile phase: A=0.1% TFA/H₂O, B=0.01% TFA/MeCN; Gradient:B=5%-95% in 1.5 min; Flow rate: 2.0 mL/min; Column: sunfire-C₁₈, 50×4.6mm, 3.5 um;

Method B: Mobile phase: A=10 mM NH₄HCO₃/H₂O, B=MeCN; Gradient: B=5%-95%in 1.5 min; Flow rate: 2.0 mL/min; Column: Xbridge-C₁₈, 50×4.6 mm, 3.5um;

Method C: Mobile phase: A=10 mM ammonium formate/H₂O/4.9% MeCN, B=MeCN;Gradient: B=5%-100% in 2.0 min; Flow rate: 2.5 mL/min; Column: AtlantisT3 3 uM 4.6×30 mm

Method D: Mobile phase: A=0.1% formic acid/H₂O/4.9% MeCN, B=MeCN;Gradient: B=5%-100% in 2.0 min; Flow rate: 2.5 mL/min; Column: AtlantisT3 3 uM 4.6×30 mm

Method E: Mobile phase: A=0.05% TFA/H₂O, B=0.05% TFA/MeCN; Gradient:B=5%-100% in 3.0 min; Flow rate: 0.8 mL/min; Column: CAPCELL PAK C18(Shiseido, UG120, 3 mM, 2.0 mm I.D.×50 mm).

Representative Conditions of PREP-HPLC are listed here:

PREP-HPLC Condition A (Basic Mobile Phase):

Instrument: Gilson 281

Mobile Phase: A=0.01% NH₄HCO₃/H₂O, B=MeCN

Flow Rate: 40.0 mL/min

Column: AGT Venusil XBP C₁₈, 10.0 um, 30 mm×100 mm

PREP-HPLC Condition B (Basic Mobile Phase):

Instrument: Gilson 281

Mobile Phase: A=NH₃—H₂O, 10 mmol/L, B=MeCN

Flow Rate: 40.0 mL/min

Column: Waters X-Bridge, 5.0 um, 30 mm×150 mm

PREP-HPLC Condition C (Basic Mobile Phase):

Instrument: Gilson 281

Mobile Phase: A=0.01% NH₄HCO₃/H₂O, B=MeCN

Flow Rate: 30.0 mL/min

Column: Shimadzu PRC-ODS, 10.0 um, 20 mm×250 mm

Gradient: B=xx %-yy % 0.0 to 8.0 min

-   -   yy %-95% 8.0 to 8.2 min    -   95%-95% 8.2 to 11.0 min        The following table shows the relationship of representative        value (xx %-yy %) of gradient and retention time on LC-MS of        corresponding compound.        25%-30% 0.5-1.0 min        30%-50% 1.0-1.5 min        50%-70% 15-1.75 min        70%-90% 1.7-2.0 min        PREP-HPLC Condition D:        Instrument: Waters 600 pump, Waters 2996, Photodiode Array        Detector, Waters Micromass ZQ, Gilson 215 Liquid Handler.        Mobile Phase: A=0.05% TFA/H₂O, B=MeCN        Flow Rate: 36.0 mL/min        Column: Shiseido CAPCELL PAK C18, UG120, 5 uM, 20 mm I.D.×50 mm        Gradient: B=5%-100% 0.0 to 4.0 min

Method A: 2-Nitro-5-propoxy-benzamide (i-a)

A mixture of 2-nitro-5-propoxy-benzoic acid (1.97 g, 8.75 mmol) and DMF(0.1 mL) in SOCl₂ (20 mL) was stirred at 65° C. for 2 h. After thereaction was completed, the mixture was cooled to room temperature.SOCl₂ was removed in vacuo and the residue was dissolved in anhydrousCH₂Cl₂ (10 mL), which was added to NH₃—H₂O (28%) dropwise. After 1 h,the precipitate was collected and dried in vacuo to give 1.68 g of i-aas a yellow solid (85.2%). LCMS m/z=208.1 (M−16), 225.1 (M+1) (Method B)(retention time=1.88 min).

Method B: 2-Amino-5-propoxy-benzamide (ii-a)

To a mixture of 2-nitro-5-propoxy-benzamide (1.20 g, 5.36 mmol) inMeOH-H₂O (v/v, 3:1, 60 mL) was added NH₄Cl (2.84 g, 53.6 mmol) and Fe(2.99 g, 53.6 mmol). The resulting mixture was stirred at 60° C. for 3h. After the reaction was completed, the mixture was cooled to roomtemperature and the iron was filtered off. The filtrate was concentratedto 15 mL and the formed precipitate was collected and dried in vacuo togive 1.02 g of ii-a as a pale yellow solid (98%). LCMS m/z=1781 (M−16),195.1 (M+1) (Method B) (retention time=1.46 min).

Method I: 2-Amino-4-chlorobenzamide (ii-b)

To a mixture of 2-amino-4-chlorobenzoic acid (3.42 g, 20 mmol) in DMF(45 mL) was added HOBt (2.70 g, 20 mmol). After stirring for 10 min, EDChydrogen chloride (3.82 g, 20 mmol) was added to the mixture. Theresulted mixture was stirred at room temperature for 2 h. NH₄OH (28%, 5mL) was added at 0° C. with vigorous stirring. After addition, themixture was stirred at room temperature for another 2 h. The reactionmixture was added to water (200 mL) dropwise with stirring, then aprecipitate formed. The precipitate was collected and dried in vacuo togive 2.98 g of ii-b as a grey solid (87.6% yield). LCMS m/z=171.0 (M+1),173.0 (M+3) (Method B) (retention time=1.39 min). ¹H NMR (400 MHz,DMSO-d₆): δ 7.27 (d, J=9.6 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.60 (dd,J=8.4, 2.0 Hz, 1H), 5.50-5.82 (m, 4H).

Method F for Chlorinating ConditionsF1: POCl₃/N,N-dimethylbenzeneamineF2: SOCl₂/DMF/80° C.F3: SOCl₂ (4-8 equiv.)/DMF/DCM/rt-40° C.F4: Phenylphosphinic dichloride/80-120° C.F5: POCl₃/ΔF6: POCl₃/Toluene/100° C.F7: PBr₃/CH₂Cl₂/DMF/60° C.Method G for Coupling ConditionsG1: i-PrOH/85-100° C.G2: THF/refluxG3: i-AmOH/100-130° C.G4: MeOH/microwave/150° C.G5: i-AmOH/microwave/150° C.G6: THF/Et₃N/refluxG7: THF-H₂O/NaOAc/rt-60° C.G8: NaH/THFG9: n-BuLi/THFG10: LHMDS/THFG11: LDA/THFG12: KCO₃/DMF/60° C.G13: Cs₂CO₃/DMA/80° C.G14: NaOtBu/DMF/Microwave/100° C.Method J for Coupling ConditionsJ1: Pd(PPh₃)₄/t-BuOK/DioxaneJ2: Pd₂(dba)₃/Xantphos/Cs₂CO₃/Dioxane

Method C: N-(2-Carbamoyl-4-propoxy-phenyl)-nicotinamide (iii-a)

To a solution of 2-amino-5-propoxy-benzamide (760 mg, 3.91 mmol) in THF(15 mL) and Et₃N (1 mL) was added nicotinoyl chloride (607 mg, 4.30mmol) in anhydrous THF (15 min) dropwise. The resulting mixture wasstirred at room temperature for 3 h. After the reaction was completed,the volatiles were removed. The residue was washed with H₂O (10 mL). ThepH was adjusted to approximately 5 by adding dilute HCl (2N in water).The resulting solid was collected and dried in vacuo to give 1.00 g ofiii-a as a pale yellow solid (89.0%). LCMS m/z=300.1 (M+1) (Method B)(retention time=1.60 min).

Method D: 2-benzamido-5-methoxy-3-methylbenzamide (iii-b)

A 50 mL round-bottom flask was charged with nicotinic acid (41 mg, 0.33mmol, 1.0 eq.), 2-amino-5-methoxy-3-methylbenzamide (60 mg, 0.33 mmol,1.0 eq.) and HBTU (190 mg, 0.50 mmol, 1.5 eq), which were suspended in 4mL, of DMF. DIPEA (86 mg, 0.66 mmol, 2.0 eq.) was added dropwise at roomtemperature and the reaction mixture was stirred overnight. The reactionmixture was added to water (10 mL) dropwise with stirring. The mixturewas extracted with ethyl acetate. The ethyl acetate was evaporated and55 mg of the orange solid (58.5% yield) was obtained. LCMS m/z=286.1(M+1) (Method B) (retention time=1.24 min).

Method E: 6-Propoxy-2-pyridin-3-yl-1H-quinazolin-4-one (iv-a)

A mixture of N-(2-carbamoyl-4-propoxy-phenyl)-nicotinamide (980 mg, 3.27mmol) in EtOH (20 mL) was treated with NaOH (654 mg, 16.37 mmol). Theresulting mixture was stirred at room temperature for 18 h. After thereaction was completed, the volatiles were removed in vacuo. The residuewas partitioned between H₂O (50 mL) and ethyl acetate (50 mL). Theaqueous layer was neutralized to pH 7 by slowly adding aq. citric acidand then a precipitate formed. The precipitate was collected and driedto give 1.00 g of iv-a as a grey solid (quantitative yield). LCMSm/z=282.1 (M+1) (Method B) (retention time=1.60 min).

Method F1: 4-Chloro-6-propoxy-2-pyridin-3-yl-quinazoline (v-a)

(This method is representative of method F1, F2, F3 and F4. These threemethods can be implemented in a similar way except for substitution ofthe appropriate chlorinating reagent, solvent and temperature) To amixture of 6-propoxy-2-pyridin-3-yl-1H-quinazolin-4-one (1.00 g, 3.56mmol) in POCl₃ (10 mL) was added N,N-dimethylaniline (0.1 mL). Theresulting mixture was stirred at 120° C. for 2 h. After the reaction wascompleted, POCl₃ was removed in vacuo, and the residue was added toice-water slowly. The pH was adjusted to around 7 by slowly addingNaHCO₃ (sat.) at 0 (C. The resultant solid was collected and purified bychromatography on silica gel eluted with petroleum ether/ethyl acetate(v/v=4:1 to 1:1) to give 580 mg of v-a as a pale yellow solid (54.7%).

Method F5: 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (v-c)

In a sealed tube, phosphorus oxychloride (11 mL, 120 mmol) was added to6-methoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one (2.70 g, 10.66 mmol). Themixture was refluxed at 120° C. for 12 h. After cooling, the remainingphosphorus oxychloride was removed in vacuo to leave a tan solid. Thisresidue was added to an ice-water mixture (100 mL) with cooling andallowed to stir. The pH of the suspension was adjusted to about pH 9 viadropwise addition of 28% ammonium hydroxide, and stirring was continuedfor 30 mins. The resulting solid was filtered to give the desiredproduct as a tan solid (2.55 g, 9.39 mmol, 88%). LC-MS m/z=272.0 (M+1)(retention time=2.05) ¹H NMR (300 MHz, DMSO) δ 9.55 (s, 1H), 8.81-8.64(m, 2H), 8.09 (d, J=9.2 Hz, 1H), 7.78 (dd, J=9.2, 2.8 Hz, 1H), 7.61 (dd,J=7.9, 4.8 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 4.00 (s, 3H).

Method F6: 6-Bromo-4-chloro-8-fluoro-2-(pyridin-3-yl)quinazoline (v-d)

To a suspension of 6-bromo-8-fluoro-2-(pyridin-3-yl)quinazolin-4-ol(6.16 g, 0.0192 mol) in toluene (60 mL) was added phosphorus oxychloride(5.30 ml, 0.0579 mol) at room temperature. The mixture was refluxed for3 h. The solvent was evaporated and water was added to the residue undercooling conditions. The suspension was stirred at room temperature for30 min, the resulting precipitate was filtered and dried to give thetitle compound (6.5 g, quantitative). ¹H NMR (400 MHz, DMSO) δ 9.58 (d,J=1.6 Hz, 1H), 8.82 (dd, J=4.7, 1.5 Hz, 1H), 8.80-8.75 (m, 1H), 8.37(dd, J=9.7, 1.9 Hz, 1H), 8.34-8.29 (m, 1H), 767 (dd, J=7.8, 4.6 Hz, 1H).

Method F7: 4-Bromo-6-methoxy-2-(pyridin-3-yl)quinazoline (v-e)

To a sealed tube containing6-methoxy-2-(pyridin-3-yl)quinazolin-4(3)-one (1.30 g, 5.13 mmol) indichloromethane (20 mL) was added 1 M phosphorus tribromide indichloromethane (10.3 mL, 10.3 mmol) and DMF (2 mL). The reactionmixture was heated at 60° C. for 4 h. After cooling, excessdichloromethane was evaporated leaving a tan residue. This solid wasadded to an ice-water mixture (100 mL) with cooling and allowed to stir.The pH of the suspension was adjusted to about pH 9 via dropwiseaddition of 28% ammonium hydroxide, and stirring was continued for 30mins. The resulting solid was filtered to give the desired product as atan solid (1.49 g, 4.71 mmol, 92%). LC-MS m/z=318.3 (M+2) (retentiontime=2.19).

Method G1: 2-(6-Propoxy-2-pyridin-3-yl-quinazolin-4-ylamino)-benzamide(vi-a)

(This method is representative of method G1, G2, and G3. These threemethods can be implemented in a similar way except for substitution ofthe appropriate solvent and temperature) A mixture of4-chloro-6-propoxy-2-(pyridin-3-yl)quinazoline (90 mg, 0.3 mmol) and2-aminobenzamide (52 mg, 0.4 mmol) in i-PrOH (5 mL) was stirred at 85°C. for 18 h. The yellow precipitate was collected and washed with i-PrOH(10 mL). The solid was suspended in water (10 mL) and NH₃—H₂O (1 mL) wasadded. After filtration the solid was dried in vacuo to afford 31.0 mgof vi-a as a white solid (30.8%). LCMS m/z=400.1 (M+1) (Method B)(retention time=1.96 min). ¹H-NMR (400 MHz, DMSO-d₆): δ 9.59 (d, J=2.0Hz, 1H), 9.58 (d, J=7.6 Hz, 1H), 8.69-8.74 (m, 2H), 8.48 (s, 1H), 7.97(d, J=6.8 Hz, 2H), 7.90 (d, J=8.8 Hz 1H), 7.74 (t, J=7.6 Hz, 1H),7.56-7.61 (m, 3H), 7.20 (t, J=7.2 Hz, 1H), 4.16 (t, J=6.4 Hz, 2H), 1.86(dd, J=14.0, 6.8 Hz, 2H), 1.07 (t, J=7.2 Hz, 3H).

Method G8: 2-(6-ethoxy-2-(pyridin-3-yl)quinazolin-4-yloxy)benzamide(vii-a)

(The method G8 is representative of method G6, G7, G9, G10 and G11.These six methods can be implemented in a similar way except forsubstitution of the appropriate base, solvent and temperature) To a 2.5dram reaction vial was first added sodium hydride 60% (0.028 g, 0.700mmol) and salicylamide (0.072 g, 0.525 mmol) in DMF (2 mL). The mixturewas allowed to stir at room temperature for 1 h. Then,4-chloro-6-ethoxy-2-(pyridin-3-yl)quinazoline (0.100 g, 0.350 mmol) wasadded to the mixture, and the reaction was allowed to proceed at roomtemperature overnight. LC-MS analysis of the crude mixture showed about85% of product formed and 10% remaining starting material. Water (30 mL)was added to the mixture, and the product was extracted with chloroform(3×15 mL). The combined organic layers were dried (Na₂SO₄), filtered,and concentrated. The crude product was purified via ISCO (silica gel,97.5:2.5 CH₂Cl₂/MeOH; 12 g column) to afford 13.9 mg of the desiredproduct as a white solid (10.3%) LCMS m/z=387 (M+1) (Method C)(retention time=2.05 min). ¹H NMR (300 MHz, DMSO) δ 11.47 (s, 2H), 9.39(s, 1H), 8.66 (d, J=2.8 Hz, 1H), 8.56-8.47 (m, 1H), 8.01-7.90 (m, 2H),7.69-7.55 (m, 2H), 7.55-7.40 (m, 2H), 7.05 (t, J=7.5 Hz, 1H), 6.97 (d,J=8.2 Hz, 1H), 4.23 (q, J=6.9 Hz, 2H), 1.44 (t, J=6.9 Hz, 3H).

Method G13:4-(4-chlorophenyl)-N-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-yl)thiazol-2-amine(vi-c)

(The method G13 is representative of method G12 also. This method can beimplemented in a similar way except for substitution of the appropriatebase, solvent and temperature) To a suspension of4-chloro-6-methoxy-2-(pyridine-3-yl)quinazoline (645.2 mg, 2.375 mmol)and 2-amino-4-(4-chlorophenyl)thiazole (1050 mg, 4.98 mmol) in DMA (40mL) was added Cs₂CO₃ (2430 mg, 7.46 mmol) at room temperature. Themixture was stirred at 80° C. for 9.5 h. Water was added and aprecipitate formed which was collected by filtration and washed withH₂O. Recrystallization from acetone/DMF/methanol gave 383.6 mg of theproduct in a 36% yield as yellow solid, >98% purity by ¹H NMR). ¹H NMR(400 MHz DMSO-d₆) δ 12.52 (s, 1H), 9.78 (d, J=1.56 Hz, 1H), 8.91-8.88(m, 1H), 8.74 (dd, J=4.74, 1.60 Hz, 1H), 8.33 (brs, 1H), 8.06 (d, J=8.56Hz, 2H), 7.93 (d, J=9.08 hz, 1H), 7.89 (s, 1H), 7.66-7.59 (m, 2H), 7.55(d, J=8.56 Hz, 2H), 4.01 (s, 3H).

Method G14:4-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)-1H-pyrazole-5-carboxamide,2HCl (vi-d)

(The method G14 is representative of method G4 and G5 also. This methodcan be implemented in a similar way except for substitution of theappropriate solvent and adjustment of the temperature) To a microwavevial containing 4-bromo-6-methoxy-2-(pyridin-3-yl)quinazoline (150.0 mg,0.47 mmol) in DMF (2 mL) was added 4-amino-1H-pyrazole-5-carboxamide(66.0 mg, 0.52 mmol) and sodium tert-butoxide (50 mg, 0.52 mmol). Thereaction mixture was heated at 100° C. for 15 mins by microwaveirradiation. Water (50 mL) was added to the reaction mixture, andextracted with ethyl acetate (5×50 mL). The crude material was purifiedvia ISCO (silica, 12 g column, 93% CH₂Cl₂-7% MeOH-0.1% NH₄OH) giving theproduct as a yellow solid. The free base was then converted to the HClsalt to yield the final product as an orange solid (59.8 mg, 0.14 mmol,22%). LC-MS m/z=362.4 (M+1) (retention time=1.57) ¹H NMR (300 MHz, DMSO)δ 11.28 (s, 1H), 9.62 (d, J=1.7 Hz, 1H), 9.17 (d, J=7.8 Hz, 1H), 8.93(dd, J=5.2, 1.3 Hz, 1H), 8.60 (s, 1H), 8.05 (s, 1H), 8.03-7.94 (m, 2H),7.77 (s, 1H), 7.64 (dd, J=9.2, 2.5 Hz 1H), 7.40 (d, J=2.6 Hz, 1H), 3.97(s, 3H).

Method J1:1-(6-Methoxy-2-(pyridin-3-yl)quinazolin-4-yl)-1H-benzo[d]imidazol-2(3H)-one(vi-b)

To a 50-mL two-neck round bottom flask equipped with a reflux condenserwas added a mixture of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline(50 mg, 0.18 mmol, 1 eq.) and 1H-benzo[d]imidazol-2(3H)-one (27 mg, 0.21mmol, 1.1 eq.) in 5 mL of dry 1,4-dioxane. Pd(PPh₃)₄ (10.6 mg, 0.009mmol, 0.05 eq) and t-BuOK (41 mg, 0.36 mmol, 2 eq.) were added. Theresulting mixture was stirred at 100° C. under N₂ atmosphere overnight.After cooling, 20 mL of methanol was added. The mixture was filtered,the filtrate was concentrated in vacuo and then was purified withchromatography on silica gel (ethyl acetate/petroleum ether from 1:4 to1:2) to give the crude product, which was further purified with reversephase HPLC to afford 4.8 mg of vi-e as a pale yellow solid (7%). MSm/z=370.1 (M+1) (Method B) (retention time=1.680 min). ¹H NMR (400 MHz,DMSO-d₆): δ 11.51 (s, 1H), 8.78 (d, J=8.0 Hz, 2H), 8.17 (d, J=9.2 Hz,1H), 7.80 (dd, J=9.2, 2.8 Hz, 1H), 7.70-7.64 (m, 1H), 7.46 (d, J=2.8 Hz,1H), 7.41 (d, J=8.0 Hz, 1H), 7.20 (d, J=4.0 Hz, 2H), 7.16-7.08 (m, 1H),3.89 (s, 3H).

Method J2: 6-methoxy-N-(pyridin-2-yl)-2-(pyridin-3-yl)quinazolin-4-aminedihydrochloride (vi-e)

To a suspension of 4-chloro-6-methoxy-2-(pyridine-3-yl)quinazoline (600mg, 2.208 mmol) in dioxane (40 mL) under N₂, was addedtris(dibenzylideneacetone)dipalladium(0) (103.1 mg, 0.113 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (132.2 mg, 0.228 mmol)and cesium carbonate (1.1289 g, 3.46 mmol) at room temperature.2-Aminopyridine (229 mg, 2.43 mmol) was added and the mixture wasstirred at 100° C. for 2 h 30 min. Water was added and then aprecipitate formed. The solid was collected and washed with water. Thesolid was dissolved in CH₂Cl₂. Purification was carried out usingNH-silica gel to give the free base (649.3 mg). The free base wasconverted to the HC salt by dissolving the compound in CH₂Cl₂/MeOH and1.5 ml of 4N HCl in ethyl acetate was added and then a precipitateformed. The solid was collected and dried in vacuo (at 40 degrees on and60 degrees for ca. 3 h) and then washed with methanol. The resultingsolid was dried in vacuo at 60 degrees to give 682 mg of the desiredproduct as the HCl salt in a 77% yield as a pale yellow solid. ¹H NMR(DMSO-d₆) δ 11.14 (brs, 1H), 9.58 (s, 1H), 9.13 (dd, J=7.96 Hz, 1H),8.93 (d, J=5.24 Hz, 1H), 8.54 (d, J=4.72 Hz, 1H), 8.48 (d, J=8.32 Hz,1H), 8.28 (brs, 1H), 8.09 (brt, J=7.16 Hz, 1H), 8.02-7.96 (m, 2H), 7.65(dd, J=8.80, 2.48 Hz, 1H), 7.34 (brt, J=6.52 Hz, 1H), 4.01 (s, 3H). The1H of 2HCl was not observed.

Method J3:N-(Biphenyl-4-yl)-6-methoxy-2-(pyridin-3-yl)quinazolin-4-aminehydrochloride (vi-f)

To a suspension ofN-(4-bromophenyl)-6-methoxy-2-(pyridin-3-yl)quinazolin-4-amine (548.7mg, 1.347 mmol) and phenylboronic acid (270 mg, 2.21 mmol) indioxane/H₂O (2/1) (30 mL) under N₂ was added Na₂CO₃ (485 mg, 4.58 mmol)and tetrakis(triphenylphosphine) palladium(0) (78 mg, 0.067 mmol) atroom temperature. The mixture was stirred at 100° C. for 1 h. Water wasadded and then a precipitate formed. The solid was dissolved inmethanol/acetone at 60° C. The solution was filtrated through Celite toremove any extra palladium. The filtrate was concentrated down to give493.4 mg of a solid residue in. The solid was added to CH₂Cl₂ followedby addition of 4N HCl in ethyl acetate (0.4 mL) at room temperature toform the HCl salt. The mixture was stirred at room temperature and theresulting solid was filtered and dried in vacuo to give 435.2 mg and ayield of 73% as the HCl salt. ¹H NMR (DMSO-d6) δ 10.24 (br, 1H), 9.54(s, 1H), 8.92 (d, J=7.52 Hz, 1H), 8.82 (d, J=3.96 Hz, 1H), 8.10 (d,J=2.44 Hz, 1H), 8.03 (d, J=8.68 Hz, 2H), 7.92 (d, J=9.08 Hz, 1H), 7.84(d, J=8.68 Hz, 2H), 7.81 (m, 1, 7.77-7.75 (m, 2H), 7.62 (dd, J=9.08,2.44 Hz, 1H), 7.50 (m, 2H), 7.38 (m, 1H), 4.01 (s, 3H). The 1H of HClwas not observed.

The compounds in the following table were prepared in a manner analogousto that described in Scheme 1 and 5 (prepared according to methodprocedure A-J as designated).

TABLE 1 Puri- Meth- ty od for Salt Molecular LCMS per- Coup- NumberProduct type Mass ¹H-NMR Solvent LCMS Protocol cent ling 1

399.45 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.59 (d, J = 2.0 Hz, 1H), 9.58 (d, J= 7.6 Hz, 1H), 8.69-8.74 (m, 2H), 8.48 (s, 1H), 7.97 (d, J = 6.8 Hz,2H), 7.90 (d, J = 8.8 Hz 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.56- 7.61 (m,3H), 7.20 (t, J = 7.2 Hz, 1H), 4.16 (t, J = 6.4 Hz, 2H), 1.86 (dd, J =7.2, 6.8 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H). DMSO 400.1 (M + 1) Method B(NH4HCO3) 95 Meth- od C, G1 2

HCl 398.46 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.20 (s, 1H), 9.79 (s, 1H),9.02-9.08 (m, 2H), 8.87 (d, J = 3.2 Hz, 1H), 8.53 (s, 1H), 3.34 (d, J =8.0 Hz, 1H), 8.19 (d, J = 6.8 Hz, 1H), 7.74-7.99 (m, 5H), 7.28 (t, J =7.6 Hz, 1H), 4.92 (d, J = 4.0 Hz, 2H), 2.87 (d, J = 3.2 Hz, 6H). DMSO399.1 (M + 1) Method B (NH4HCO3) 95 Meth- od C, G1 3

HCl 424.50 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.07 (s, 1H), 9.64 (d, J = 1.6Hz, 1H), 9.15 (d, J = 8.0 Hz, 1H), 8.78 (ddd, J = 8.0, 4.0, 2.4 Hz, 1H),8.73 (dd, J = 4.4, 1.2 Hz, 1H), 8.49 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H),7.92-7.69 (m, 3H), 7.67- 7.74 (m, 2H), 7.62 (dd, J = 8.0, 4.8 Hz, 1H),7.22 (t, J = 7.6 Hz, 1H), 4.29 (s, 2H), 2.61 (brs, 4H), 1.70 (brs, 4H).DMSO 425.2 (M + 1) Method B (NH4HCO3) 95 Meth- od C, G1 4

422.43 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.87 (s, 1H), 9.52 (s, 1H), 8.67 (d,J = 5.6 Hz, 1H). 7.99 (d, J = 2.4 Hz, 1H), 7.94 (s, 1H), 7.86 (d, J =9.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.50-7.58 (m, 3H), 7.30 (t, J =34.0 Hz, 1H), 7.00 (dd, J = 8.4, 2.0 Hz, 1H), 4.16 (t, J = 6.4 Hz, 2H),1.86 (dd, J = 7.2, 6.4 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H). DMSO 423.1(M + 1) Method B (NH4HCO3) 95 Meth- od C, G1 5

HCl 408.86 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.28 (s, 1H), 9.48 (s, 1H),8.93 (d, J = 8.4 Hz, 1H), 8.85 (d, J = 4.4 Hz, 1H), 8.18 (dd, J = 7.6,2.4 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.85-7.93 (m, 3H), 7.62 (dd, J =8.8, 6.4 Hz, 1H), 7.55 (t, J = 8.8 Hz, 1H), 4.17 (t, J = 6.4 Hz, 3H),1.86 (dd, J = 7.6, 6.4 Hz, 2H), 1.06 (t, J = 7.6 Hz, 3H). DMSO  409.1,411.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 6

425.31 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.93 (s, 1H), 9.51 (s, 1H),8.68-8.71 (m, 2H), 8.16 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H),7.86 (d, J = 8.8 Hz, 1H), 7.56- 7.60 (m, 2H), 7.37 (s, 1H), 4.14 (t, J =6.4 Hz, 2H), 1.84 (dd, J = 10.4 Hz, 7.2 Hz, 2H), 1.07 (t, J = 7.6 Hz,3H). DMSO  425.0, 427.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 7

392.4 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.06 (s, 1H), 9.49 (s, 1H),8.77-8.81 (m, 2H), 8.09 (ddd, J = 10.0, 7.6. 2.4 Hz, 1H), 7.88 (d, J =9.2 Hz, 1H), 7.69-7.74 (m, 2H), 7.54-7.61 (m, 2H), 4.15 (t, J = 6.4 Hz,2H), 1.86 (dd, J = 14,0, 7.6 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H). DMSO393.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 8

425.31 ¹H-NMR (400 MHz,. DMSO-d₆): δ 10.05 (s, 1H), 9.51 (s, 1H),8.75-8.80 (m, 2H), 8.34 (d, J = 2.4 Hz, 1H), 7.96-8.00 (m, 2H), 7.88 (d,J = 9.2 Hz, 1H), 7.68-7.75 (m, 2H), 7.59 (dd, J = 9.2, 2.8 Hz, 1H), 4.15(t, J = 6.4 Hz, 2H), 1.86 (dd, J = 7.2, 6.8 Hz, 2H), 1.06 (t, J = 7.6Hz, 3H). DMSO  425.0, 427.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G19

415.44 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.03 (s, 1H), 9.59 (d, J = 1.2 Hz,1H), 9.15 (d, J = 8.4 Hz, 1H), 8.69-8.74 (m, 2H), 8.49 (s, 1H),7.96-8.06 (m, 2H), 7.90 (d, J = 9.2 Hz, 1H), 7.56-7.63 (m, 3H), 7.20 (t,J = 8.0 Hz, 1H), 4.31 (t, J = 4.0 Hz, 2H), 3.79 (t, J = 4.8 Hz, 2H),3.31 (s, 3H). DMSO 416.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 10

438.43 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.86 (s, 1H), 9.53 (s, 1H),8.66-8.68 (m, 2H), 8.02 (d, J = 2.8 Hz, 1H), 7.95 (t, J = 2.0 Hz, 1H),7.86 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.48-7.60 (m, 3H),7.30 (t, J = 74.4 Hz, 1H), 7.00 (dd, J = 8.0, 2.0 Hz, 1H), 4.33 (t, J =4.8 Hz, 2H), 3.79 (t, J = 4.4 Hz, 2H), 3.37 (s, 3H). DMSO 439.1 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 11

HCl 424.86 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.27 (s, 1H), 9.48 (s, 1H),8.93 (d, J = 8.4 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 8.19 (dd, J = 6.8,2.4 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.85-7.93 (m, 3H), 7.64 (dd, J =9.2, 6.8 Hz, 1H), 7.55 (t, J = 8.8 Hz, 1H), 4.34 (t, J = 4.4 Hz, 2H),3.78 (t, J = 4.4 Hz, 2H), 3.31 (s, 3H). DMSO  425.1, 427.1 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 12

397.43 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.07 (s, 1H), 9.50 (s, 1H), 8.78(dd, J = 17.6, 7.6 Hz, 1H), 8.39 (s, 1H), 8.26 (dd, J = 8.0, 2.0 Hz,1H), 8.02 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.61-7.73 (m,4H), 4.34 (t, J = 4.8 Hz, 2H), 3.79 (t, J = 4.4 Hz, 2H), 3.35 (s, 3H).DMSO 398.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 13

408.4 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.86 (s, 1H), 9.50 (d, J = 1.6 Hz,1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 8.64 (dt, J = 8.0, 1.6 Hz, 1H),8.12 (ddd, J = 13.2, 7.2, 2.4 Hz, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.86(d, J = 9.2, 1H), 7.69-7.72 (m, 1H), 7.52-7.60 (m, 3H), 4.31 (t, J = 4.0Hz, 2H), 3.76-3.80 (m, 2H), 3.37 (s, 3H). DMSO 409.1 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 14

441.31 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.90 (s, 1H), 9.52 (d, J = 1.2 Hz,1H), 8.64-8.68 (m, 1H), 8.37 (d, J = 2.8 Hz, 1H), 7.98 (d, J = 2.4 Hz,1H), 7.96 (dd, J = 10.6, 2.4 Hz, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.74 (d,J = 9.2 Hz, 1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.55 (dd, J = 8.0, 4.8Hz, 1H), 4.31 (t, J = 4.08 Hz, 2H), 3.78 (t, J = 4.4 Hz, 2H), 3.37 (s,3H). DMSO  441.0, 443.0 (M + 1) 221.9 (M/2 + 1) Method A (TFA) 95Meth-od C, G1 15

441.31 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.93 (s, 1H), 9.53 (d, J = 1.6 Hz,1H), 8.66-8.70 (m, 2H), 8.18 (s, 1H), 8.17 (s, 1H), 7.99 (d, J = 2.4 Hz,1H), 7.89 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 8.8, 2.4 Hz, 1H), 7.56 (dd,J = 7.6, 4.8 Hz, 1H), 7.39 (t, J = 2.0 Hz, 1H), 4.33 (t, J = 4.8 Hz,2H), 3.79 (t, J = 4.4 Hz, 2H), 3.37 (s, 3H). DMSO  441.1, 443.1 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 16

HCl 375.79 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.34 (s, 1H), 9.53 (d, J = 1.2Hz, 1H), 9.16 (d, J = 1.2 Hz, 1H), 8.74 (dd, J = 4.0, 1.6 Hz, 1H),8.68-8.69 (m, 2H), 8.20-8.28 (m, 2H), 8.00 (d, J = 8.4 Hz, 1H),7.89-7.93 (m, 1H), 7.55-7.61 (m, 2H). DMSO  376.0, 378.0 (M + 1) MethodB (NH4HCO3) 95 Meth-od C, G1 17

393.8 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.37 (s, 1H), 9.54 (d, J = 1.6 Hz,1H), 9.09 (s, 1H), 8.69 (d, J = 10.0 Hz, 1H), 8.68 (d, J = 8.0 Hz, 1H),8.23-8.27 (m, 2H), 8.11 (s, 1H), 8.78 (s, 2H), 7.50-7.58 (m, 3H). DMSO 394.1, 396.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 18

HCl 394.79 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.81 (s, 1H), 9.48 (d, J = 0.3Hz, 1H), 9.23 (d, 0.8 Hz, 1H), 8.69 (d, J = 10.0 Hz, 1H), 8.68 (d, J =8.0 Hz, 1H), 8.23-8.27 (m, 2H), 8.11 (s, 1H), 8.78 (s, 2H), 7.50- 7.58(m, 3H). DMSO  395.0, 397.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G119

422.38 1H-NMR (400 MHz, DMSO-d₆): δ 10.11 (brs, 1H), 9.48 (s, 1H), 8.79(d, J = 4.8 Hz, 1H), 8.83 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H),8.02 (d, J = 2.4 Hz, 1H), 7.88-7.90 (m, 1H), 1.77 (d, J = 8.0 Hz, 1H),7.52-7.62 (m, 3H), 4.27 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H).DMSO 423.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 20

HCl 408.81 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 1H), 9.52 (d, J = 1.6Hz, 1H), 9.32 (d, J = 1.6 Hz, 1H), 9.01 (d, J = 4.8 Hz, 1H), 8.91 (d, J= 5.2 Hz, 1H), 8.39 (dd, J = 8.4, 1.6 Hz, 1H), 8.17 (dd, J = 8.3, 2.0Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.90- 7.95 (m, 2H), 7.55 (t, J = 9.2Hz, 1H), 3.98 (s, 3H). DMSO  409.1, 411.1 (M + 1) Method B (NH4HCO3) 95Meth-od C, G1 21

399.45 ¹H-NMR (400 MHz, DMSO-d₆) δ 12.94 (s, 1H), 9.56 (s, 1H), 9.14 (d,J = 8.0 Hz, 1H), 8.83-8.66 (m, 2H), 8.48 (s, 1H), 8.06-7.91 (m, 2H),7.76-7.58 (m, 2H), 7.35 (s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.18 (t, J =7.2 Hz, 1H), 4.15 (q, J = 6.8 Hz, 2H), 2.64 (s, 3H), 1.43 (t, J = 6.8Hz, 1H). DMSO 400.1 (M + 1) Method B (NH4HCO3) 95 Meth-od D, G1 22

440.42 ¹H-NMR (400 MHz, DMSO-d₆) δ 9.84 (s, 1H), 9.55 (d, J = 1.2 Hz,1H), 8.73-8.60 (m, 2H), 8.14 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.80 (d,J = 2.4 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.53 (dd, J = 7.6, 4.8 Hz,1H), 7.45 (d, J = 1.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.23 (q, J =6.8 Hz, 2H), 2.70 (s, 3H), 1.44 (t, J = 6.8 Hz, 3H) DMSO 440.9 (M + 1)Method A (TFA) 95 Meth-od D, G1 23

405.81 ¹H-NMR (400 MHz, DMSO-d₆) δ 10.08 (s, 1H), 9.42 (s, 1H), 8.68 (d,J = 3.6 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 8.15 (dd, J =6.8, 2.4 Hz, 1H), 8.04 (s, 1H), 7.93-7.78 (m, 1H), 7.54 (td, J = 8.3,6.9 Hz, 2H), 4.08 (s, 3H) DMSO  406.1, 408.1 (M + 1) Method B (NH4HCO3)95 Meth-od C, G1 24

493.92 ¹H-NMR (400 MHz, DMSO-d₆) δ 10.00 (s, 1H), 9.49-9.51 (m, 1H),8.62-8.70 (m, 2H), 8.21 (dd, J = 6.8, 2.8 Hz, 1H), 8.03 (s, 1H),7.87-7.91 (m, 1H), 7.75 (s, 1H), 7.53-7.59 (m, 2H), 4.02 (s, 3H),3.64-3.73 (m, 4H), 3.49-3.58 (m, 2H), 3.14-3.22 (m, 2H). DMSO  494.1,496.1 (M + 1) Method B (NH4HCO4) 95 Meth-od C, G1 25

TFA 369.38 ¹H-NMR (400 MHz, DMSO-d₆): δ 11.51 (s, 1H), 8.78 (d, J = 8.0Hz, 2H), 8.17 (d, J = 9.2 Hz, 1H), 7.80 (dd, J = 9.2, 2.8 Hz, 1H),7.70-7.64 (m, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H),7.20 (d, J = 4.0 Hz, 2H), 7.16-7.08 (m, 1H), 3.89 (s, 3H). DMSO 370.1(M + 1) Method B (NH4HCO3) 95 Meth-od C, J1 26

408.4 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.87 (s, 1H), 8.53 (dd, J = 4.7, 1.5Hz, 1H), 8.23 (d, J = 6.8 Hz, 1H), 8.00 (d, J = 2.6 Hz, 1H), 7.8 (t, J =2.1 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.73 (dd, J = 8.2, 1.2 Hz, 1H),7.58 (dd, J = 9.1, 2.6 Hz, 1H), 7.41- 7.25 (m, 3H), 7.24 (t, J = 74.0Hz, 1H), 6.96 (dd, J = 8.0, 2.2 Hz, 1H), 3.99 (s, 3H), 2.75 (s, 3H).DMSO 409.1 (M + 1) Method B (NH4HCO3) 95 Meth-od D, G1 27

385.42 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.09 (s, 1H), 9.08 (d, J = 7.8 Hz,1H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H), 8.49 (s, 1H), 8.22 (dd, J = 7.8,.1.7 Hz, 1H), 8.01 (s, 1H), 7.95 (dd, J = 7.9, 1.2 Hz, 1H), 7.87 (d, J =9.6 Hz, 1H), 7.66-7.58 (m, 3H), 7.40 (dd, J = 7.7, 4.8 Hz, 1H), 7.15(dd, J = 11.5, 4.4 Hz, 1H), 3.99 (s, 3H), 2.77 (s, 3H). DMSO 386.1(M + 1) Method B (NH4HCO3) 95 Meth-od D, G1 28

394.83 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.10 (s, 1H), 8.63 (d, J = 4.1 Hz,1H), 8.43 (d, J = 7.6 Hz, 1H), 8.15 (dd, J = 6.8, 2.5 Hz, 1H), 8.03 (d,J = 2.3 Hz, 1H), 7.88-7.78 (m, 2H), 7.58 (ddd, J = 12.5, 8.3, 4.1 Hz,2H), 7.49 (t, J = 9.1 Hz, 1H), 3.99 (s, 3H), 2.80 (s, 3H). DMSO  395.1,397.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 29

HCl 440.5 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.19 (s, 1H), 11.12-10.93 (m,1H), 9.83 (d, J = 1.5 Hz, 1H), 9.21 (d, J = 7.8 Hz, 1H), 9.01 (d, J =7.8 Hz, 1H), 8.93-8.89 (m, 1H), 8.53 (s, 1H), 8.36 (dd, J = 11.8, 7.9Hz, 2H), 8.02-7.73 (m, 6H), 7.29 (d, J = 8.02 Hz, 1H), 5.01 (s, 2H),3.95-3.81 (m, 4H), 3.37 (s, 4H). DMSO 441.2 (M + 1) Method B (NH4HCO3)95 Meth-od C, G1 30

HCl 449.91 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.05 (s, 1H), 9.56 (s, 1H),8.73-8.66 (m, 2H), 8.47 (d, J = 8.1 Hz, 1H), 8.28 (dd, J = 6.8, 2.5 Hz,7.99-7.90 (m, 2H), 7.67-7.50 (m, 3H), 4.16 (s, 2H), 3.62 (s, 4H), 2.53(s, 4H). DMSO  450.1, 452.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G131

400.33 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.47 (d, J = 2.0 Hz, 2H), 8.70 (dd,J = 4.3, 1.6 Hz, 1H), 8.65-8.59 (m, 1H), 8.06 (s, 1H), 7.91 (dt, J =8.1, 6.0 Hz, 1H), 7.82 (dd, J = 8.2, 1.2 Hz, 1H), 7.76 (d, J = 8.4 Hz,1H), 7.59 (t, J = 8.2 Hz, 1H), 7.51 (ddd, J = 20.0, 10.0, 6.4 Hz, 2H),7.21 (d, J = 8.4 Hz, 1H). DMSO 401.1 (M + 1) Method B (NH4HCO3) 95Meth-od C, G1 32

HCl 368.77 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.53 (d, J = 11.3 Hz, 1H), 9.44(d, J = 1.2 Hz, 1H), 8.84-8.79 (m, 2H), 8.09 (dd, J = 6.8, 2.6 Hz, 1H),7.97-7.89 (m, 1H),. 7.85-7.75 (m, 3H), 7.57-7.47 (m, 2H). DMSO  369.1,371.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 33

HCl 359.36 ¹H-NMR (400 MHz, DMSO-d₆): δ 12.21 (d, J = 12.1 Hz, 1H), 9.53(d, J = 1.2 Hz, 1H), 8.99 (d, J = 8.1 Hz, 1H), 8.39 (d, J = 4.2 Hz, 1H),8.71 (d, J = 7.9 Hz, 1H), 8.35 (s, 1H), 7.97-7.76 (m, 5H), 7.72- 7.65(m, 1H), 7.50 (dd, J = 12.1, 7.5 Hz, 1H), 7.29 (t, J = 7.1 Hz, 1H). DMSO360.2 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 34

382.34 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.49 (d, J = 1.8 Hz, 1H), 9.42 (s,1H), 8.71 (dd, J = 4.6, 1.3 Hz, 1H), 8.65 (d, J = 7.8 Hz, 1H), 7.90 (dd,J = 15.8, 9.7 Hz, 2H), 7.73 (dd, J = 19.0, 8.26 Hz, 2H), 7.56- 7.12 (m,4H), 7.04 (dd, J = 8.2, 1.8 Hz, 1H). DMSO 383.1 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 35

HCl 400.33 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.43 (s, 1H), 9.52 (s, 1H),8.89 (d, J = 8.2 Hz, 1H), 8.85 (d, 4.2 Hz, 1H), 8.78 (dd, J = 9.2, 5.9Hz, 1H), 8.09 (s, 1H), 7.95 (dd, J = 8.2, 1.2 Hz, 1H), 7.80 (dd, J =7.9, 5.2 Hz, 1H), 7.72-7.58 (m, 3H), 7.21 (d, J = 8.4 Hz, 1H). DMSO401.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 36

HCl 405.84 ¹H-NMR (400 MHz,. DMSO-d₆): δ 10.74- 10.48 (m, 1H), 9.36 (d,J = 1.6 Hz, 1H), 8.95 (d, J = 8.2 Hz, 1H), 8.89-8.85 (m, 1H), 8.05 (d, J= 1.7 Hz, 1H), 8.02 (d, J = 9.15 Hz, 1H), 7.93-7.86 (m, 2H), 7.73- 7.63(m, 3H), 7.60-7.52 (m, 2H), 3.98 (s, 3H). DMSO  406.1, 408.1 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 37

HCl 359.36 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.61 (s, 1H), 9.00 (dd, J =15.4, 8.2 Hz, 2H), 8.36 (d, J = 4.13 Hz, 1H), 8.52 (s, 1H), 8.04-7.94(m, 3H), 7.86-7.70 (m, 4H), 7.26 (dd, J = 11.2, 4.2 Hz, 1H). DMSO 360.1(M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 38

HCl 368.77 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.22 (s, 1H), 9.52 (s, 1H),8.73 (d, J = 3.6 Hz, 1H), 8.69 (td, J = 8.0, 1.8 Hz, 1H), 8.38 (d, J =8.4 Hz, 1H), 8.25 (dd, J = 6.8, 2.6 Hz, 1H), 7.91 (ddd, J = 9.0, 4.2,2.6 Hz, 1H), 7.79 (dd, J = 9.8, 7.9 Hz, 1H), 7.67 (dd, J = 8.2, 5.2 Hz,1H), 7.61-7.53 (m, 2H). DMSO  369.0, 371.0 (M + 1) Method B (NH4HCO3) 95Meth-od C, G1 39

HCl 400.33 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.47 (s, 1H), 9.52 (d, J = 1.4Hz, 1H), 9.04 (d, J = 8.0 Hz, 1H), 8.92 (dd, J = 5.2, 1.2 Hz, 1H), 8.52(d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 7.97 (d, J = 1.2 Hz, 2H), 7.86-7.80(m, 1H), 7.74-7.68 (m, 1H), 7.62 (t, J = 8.2 Hz, 1H), 7.22 (d, J = 8.4Hz, 1H). DMSO 401.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 40

360.34 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.68 (d,. J = 1.6 Hz, 1H), 8.82 (t,J = 7.9, 1.8 Hz, 1H), 8.71 (dd, J = 4.6, 1.6 Hz, 1H), 8.22 (d, J = 8.2Hz, 1H), 7.87 (dd, J = 7.8, 1.9 Hz, 1H), 7.73 (dd, J = 9 2, 7.8 Hz, 1H),7.59 (dt, J = 8.1, 5.0 Hz, 2H), 7.21-7.15 (m, 1H), 6.66 (d, J = 8.2 Hz,1H), 6.54 (t, J = 7.4 Hz, 1H). DMSO 360.9 (M + 1), 382.9 (M + 23) MethodB (NH4HCO3) 95 Meth-od C, G9 41

380.08 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.56 (brs, 1H), 9.62 (d, J = 1.2Hz, 1H), 9.05 (d, J = 8.4 Hz, 1H), 9.00 (dd, J = 1.6, 4.8 Hz, 1H), 8,71(d, J = 9.2 Hz, 1H), 8.31 (dd, J = 2.0, 7.2 Hz, 1H), 8.02-7.99 (m, 2H),7.66 (t, J = 9.2 Hz, 1H), 7.54 (s, 1H), 7.50 (dd, J = 2.4, 9.2 Hz, 1H),4.11 (s, 3H). DMSO  381.1, 383.1 (M + 1) Method B (NH4HCO3) 95 Meth-odC, G1 42

476.67 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.40 (s, 1H), 9.51 (s, 1H), 8.93(d, J = 8.0 Hz, 1H), 8.88 (d, J = 4.8 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H),8.35 (d, J = 1.6 Hz, 1H), 8.20 (dd, J = 4.4, 6.8 Hz, 1H), 8.04 (dd, J =7.2, 8.8 Hz, 1H), 7.93-7.86 (m, 2H), 7.35 (t, J = 9.2 Hz, 1H). DMSO 477.0, 499.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 43

429.67 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.46 (s, 1H), 9.49 (s, 1H), 8.95(d, J = 8.1 Hz, 1H), 8.89 (d, J = 4.97 Hz, 1H), 8.60 (d, J = 8.9 Hz,1H), 8.19 (dd, J = 6.8, 2.6 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H), 7.96-7.83(m, 3H), 7.53 (t, J = 9.0 Hz, 1H). DMSO  429.0, 430.9, 433.0 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 44

HCl 385.42 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.05 (s, 1H), 9.44 (d, J = 1.7Hz, 1H), 9.16-8.91 (m, 2H), 8.03-7.89 (m, 3H), 7.88-7.82 (m, 1H),7.75-7.68 (m, 1H), 7.67-7.60 (m, 2H), 7.25 (t, J = 7.6 Hz, 1H), 4.00 (s,3H), 2.74 (s, 3H). DMSO 386.0 (M + 1) 193.4 (M/2 + 1) Method A (TFA) 95Meth-od C, G1 45

HCl 408.4 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.37-10.12 (m, 1H), 9.35 (d, J =1.8 Hz, 1H), 8.95 (dd, J = 4.6, 3.4 Hz, 1H), 8.09 (d, J = 2.3 Hz, 1H),7.92 (d, J = 9.1 Hz, 1H), 7.87 (s, 1H), 7.84-7.74 (m, 2H), 7.62 (dd, J =9.1, 2.6 Hz, 1H), 7.54 (t, J = 8.2 Hz, 1H), 7.32 (t, J = 74.0 Hz, 1H),7.05 (dd, J = 8.3, 1.9 Hz, 1H), 4.00 (s, 3H), 2.72 (s, 3H). DMSO 409.0(M + 1) 205.0 (M/2 + 1) Method A (TFA) 95 Meth-od C, G1 46

HCl 394.83 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.27 (brs, 1H), 9.32 (d, J =1.7 Hz, 1H), 8.93 (d, J = 7.5 Hz, 1H), 8.19 (dd, J = 6.8, 2.5 Hz, 1H),8.07 (d, J = 2.3 Hz, 1H), 7.88-7.92 (m, 2H), 7.84 (d, J = 8.1 Hz, 1H),7.62 (dd, J = 9.2, 2.5 Hz, 1H), 7.54 (t, J = 9.1 Hz, 1H), 4.00 (s, 3H),2.72 (s, 3H). DMSO  395.0, 397.0 (M + 1)  197.8, 198.8 (M/2 + 1) MethodA (TFA) 95 Meth-od C, G1 47

HCl 378.37 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.58-10.30 (m, 1H), 9.32 (d, J= 1.9 Hz, 1H), 9.04 (d, J = 7.9 Hz, 1H), 8.17-8.04 (m, 2H), 7.95 (d, J =9.0 Hz, 2H), 7.73-7.66 (m, 1H), 7.63 (dd, J = 9.2, 2.6 Hz, 1H),7.60-7.50 (m, 1H), 4.01 (s, 3H), 2.76 (s, 3H). DMSO 379.0 (M + 1) 190.0(M/2 + 1) Method A (TFA) 95 Meth-od C, G1 48

HCl 411.28 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.29 (s, 1H), 9.33 (d, J = 1.7Hz, 1H), 9.04-8.89 (m, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 2.4Hz, 1H), 7.97 (dd, J = 8.8, 2.5 Hz, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.85(d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 9.1, 2.5Hz, 1H), 4.00 (s, 3H), 2.73 (s, 3H). DMSO  411.0, 413.0 (M + 1)  205.0,206.9 (M/2 + 1) Method A (TFA) 95 Meth-od C, G1 49

411.28 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.30 (s, 1H), 9.31 (d, J = 1.5 Hz,1H), 8.94 (d, J = 7.3 Hz, 1H), 8.13 (d, J = 1.7 Hz, 2H), 8.07 (d, J =2.3 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.61(dd, J = 9.1, 2.6 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 4.00 (s, 3H), 2.72(s, 3H). DMSO  411.0, 413.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G150

HCl 389.84 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.09 (s, 1H), 9.38 (s, 1H),9.16 (d, J = 8.4 Hz, 1H), 8.83 (d, J = 8.3 Hz, 1H), 8.50 (s, 1H), 8.20(d, J = 8.8 Hz, 1H), 8.05-7.99 (m, 2H), 7.97 (d, J = 7.9 Hz, 1H), 7.92(s, 1H), 7.81 (dd, J = 8.8, 2.0 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.28(t, J = 7.6 Hz, 1H), 2.82 (s, 3H). DMSO  390.1, 392.1 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 51

HCl 412.82 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.49 (s, 1H), 9.35 (d, J = 1.7Hz, 1H), 9.08 (dd, J = 8.3, 1.5 Hz, 1H), 8.75 (d, J = 9.0 Hz, 1H), 8.02(d, J = 2.1 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.87 (s, 1H), 7.80 (dd, J= 9.0, 2.0 Hz, 2H), 7.53 (t, J = 8.2 Hz, 1H), 7.31 (t, J = 74.0 Hz, 1H),7.06 (dd, J = 8.1, 2.0 Hz, 1H), 2.79 (s, 3H). DMSO  413.0, 415.0 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 52

399.25 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.49 (s, 1H), 9.32 (d, J = 1.7 Hz,1H), 9.00 (d, J = 8.4 Hz, 1H), 8.69 (d, J = 8.9 Hz, 1H), 8.20 (dd, J =6.8, 2.6 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.96-7.86 (m, 2H), 7.80 (dd,J = 8.9, 2.1 Hz, 1H), 7.53 (t, J = 9.1 Hz, 1H), 2.76 (s, 3H). DMSO 399.0, 401.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 53

HCl 382.79 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.32 (d, J = 1.7Hz, 1H), 9.07 (dd, J = 8.2, 1.2 Hz, 1H), 8.73 (d, J = 8.9 Hz, 1H), 8.08(ddd, J = 13.0, 7.5, 2.6 Hz, 1H), 8.00 (dd, J = 8.9, 5.2 Hz, 2H), 7.80(dd, J = 8.9, 2.1 Hz, 1H), 7.71 (dd, J = 6.1, 2.9 Hz, 1H), 7.54 (dd, J =19.7, 9.2 Hz, 1H), 2.78 (s, 3H) DMSO  383.0, 385.0 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 54

HCl 415.7 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H), 9.30 (d, J = 1.7Hz, 1H), 9.07 (dd, J = 8.3, 1.8 Hz, 1H), 8.75 (d, J = 9.0 Hz, 1H), 8.29(d, J = 2.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H),7.96 (dd, J = 8.3, 2.5 Hz, 1H), 7.77 (dd, J = 8.9, 2.1 Hz, 1H), 7.70 (d,J = 8.8 Hz, 1H), 2.81 (s, 3H). DMSO  415.0,  417.0, 419.0 (M + 1) MethodB (NH4HCO3) 95 Meth-od C, G1 55

HCl 415.7 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.32 (s, 1H), 9.01(dd, J = 8.0, 1.8 Hz, 1H), 8.72 (d, J = 9.0 Hz, 1H), 8.11 (d, J = 1.8Hz, 2H), 8.01 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.80 (dd, J= 8.9, 2.0 Hz, 1H), 2.78 (s, 3H). DMSO  415.0,  417.0, 419.0 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G11 56

379.36 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.16 (s, 1H), 9.47 (s, 1H), 8.79(dd, J = 8.9, 7.1 Hz, 2H), 7.91 (s, 1H), 7.84-7.77 (m, 2H), 7.76-7.68(m, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.51 (t, J = 8.2 Hz, 1H), 7.39 (dd, J= 8.9, 2.2 Hz, 1H), 7.29 (t, J = 74.0 Hz, 1H), 7.00 (dd, J = 8.1, 2.1Hz, 1H), 4.23 (brs, 2H). DMSO 380.1 (M + 1) Method B (NH4HCO3) 95Meth-od C, G1 57

HCl 463.48 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.43-10.20 (m, 2H), 9.72 (s,1H), 8.89-8.67 (m, 3H), 8.29-8.21 (m, 1H), 7.97 (s, 1H), 7.87-7.80 (m,1H), 7.81-7.73 (m, 1H), 7.63-7.46 (m, 2H), 7.30 (t, J = 74.0 Hz, 1H),7.08-6.98 (m, 1H), 5.00 (s, 2H), 4.05-3.65 (m, 4H), 3.39-3.36 (m, 4H).DMSO 464.2 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 58

HCl 399.45 ¹H-NMR (400 MHz, DMSO-d₆) δ 12.53 (s, 1H), 9.30 (d, J = 1.6Hz, 1H), 3.03-8.96 (m, 1H), 8.94-8.88 (m, 1H), 8.71 (d, J = 8.4 Hz, 1H),7.91-7.83 (m, 3H), 7.67-7.55 (m, 3H), 7.25 (t, J = 7.2 Hz, 1H), 3.98 (s,3H), 2.80-2.74 (m, 6H). DMSO 400.1 (M + 1) Method B (NH4HCO3) 95 Meth-odC, G1 59

HCl 389.38 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.27 (s, 1H), 9.23 (s, 1H),8.98 (d, J = 5.2 Hz, 1H), 8.91 (d, J = 8.0 Hz, 1H), 8.54 (dd, J = 12.0,2.6 Hz, 1H), 8.48 (s, 1H), 8.07 (dd, J = 3.0, 5.6 Hz, 1H), 7.97-7.93 (m,2H), 7.66 (d, J = 9.0 Hz, 1H), 7.37 (dd, J = 9.0, 2.4 Hz, 1H), 7.13 (d,J = 2.0 Hz, 1H), 6.91 (dt, J = 8.4, 2.6 Hz, 1H), 3.80 (s, 3H). DMSO390.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 60

415.70 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.13 (s, 1H), 9.48 (s, 1H), 8.87(dd, J = 14.0, 6.2 Hz, 2H), 8.54 (d, J = 1.7 Hz, 1H), 8.10 (d, J = 1.8Hz, 2H), 7.89-7.78 (m, 2H), 7.37 (t, J = 1.8 Hz, 1H), 2.70 (s, 3H). DMSO 414.9,  416.9, 419.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 61

415.70 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.10 (s, 1H), 9.44 (s, 1H), 8.86(d, J = 7.8 Hz, 1H), 8.79 (d, J = 4.5 Hz, 1H), 8.50 (d, J = 1.7 Hz, 1H),8.23 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 8.8, 2.4 Hz, 1H), 7.83-7.71 (m,2H), 7.62 (d, J = 8.8 Hz, 1H), 2.62 (s, 3H) DMSO  414.9,  416.9, 418.9(M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 62

412.82 ¹H-NMR (400 MHz, DMSO-d₆): δ: 10.02 (s, 1H), 9.58 (d, J = 1.8 Hz,1H), 8.76-8.67 (m, 2H), 8.59 (d, J = 1.8 Hz, 1H), 7.96 (s, 1H), 7.82 (d,J = 6.6 Hz, 2H), 7.54 (ddd, J = 16.4, 10.0, 6.4 Hz, 2H), 7.30 (t, J =74.0 Hz, 1H), 7.01 (dd, J = 8.0, 2.0 Hz, 1H), 2.74 (s. 3H). DMSO  413.0,415.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 63

389.84 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.15 (s, 1H), 9.58 (s, 1H), 9.03(d, J = 0.8 Hz, 1H), 8.78-8.84 (m, 2H), 8.50 (s, 1H), 7.95-8.03 (m, 3H),7.80 (s, 1H), 7.70-7.74 (m, 2H), 7.23 (d, J = 7.2 Hz, 1H), 2.70 (s, 3H).DMSO  391.0, 392.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 64

371.82 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.31 (s, 1H), 9.48 (d, J = 1.2 Hz,1H), 9.01 (d, J = 8.4 Hz, 1H), 8.90 (d, J = 4.6 Hz, 1H), 8.61 (d, J =1.6 Hz, 1H), 8.33 (s, 1H), 8.27 (dd, J = 6.0, 2.0 Hz, 1H), 7.95-7.63 (m,3H), 2.70 (s, 3H). DMSO 372.0 373.1 (M + 1) Method B (NH4HCO3) 95Meth-od C, G1 65

476.67 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.28 (s, 1H), 9.46 (d, J = 1.2 Hz,1H), 9.01 (d, J = 1.2 Hz, 1H), 8.83 (dd, J = 8.4, 1.6 Hz, 2H), 8.19-8.14(m, 2H), 7.89-7.49 (m, 2H). DMSO  476.9, 478.9 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 66

399.25 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.03 (s, 1H), 8.54 (s, 1H),8.71-8.67 (m, 2H), 8.53 (s, 1H), 8.26 (dd, J = 6.8 Hz, 2.4 Hz, 1H), 7.83(s, 1H), 7.58-7.52 (m, 2H), 2.72 (s, 3H). DMSO  399.0, 401.0 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 67

382.79 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.04 (s, 1H), 9.51 (d, J = 1.2 Hz,1H), 8.72-8.69 (m, 2H), 8.53 (d, J = 2.0 Hz, 1H), 8.08 (ddd, J = 9.2,7.6, 2.4 Hz, 1H), 7.79-7.48 (m, 4H), 2.69 (s, 3H). DMSO  383.0, 385.0(M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 68

HCl 399.45 ¹H-NMR (400 MHz, DMSO-d6): δ 13.02 (s, 1H), 9.59 (s, 1H) ,9.09 (d, J = 8.0 Hz, 1H), 8.96 (d, J = 8.4 Hz, 1H) , 8.91 (d, J = 4.61Hz, 1H), 8.48 (s, 1H), 7.97 (dd, J = 8.0, 2.8 Hz, 4H), 7.72 (t, J = 7.6Hz, 1H), 7.64-7.61 (m, 2H), 7.26 (t, J = 7.6 Hz, 1H), 4.88-4.82 (m, 1H),1.43 (d, J = 6.0 Hz, 6H). DMSO 400.1 (M + 1) Method B (NH4HCO3) 95Meth-od C, G1 69

HCl 422.43 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H), 9.51 (s, 1H),9.09 (d, J = 7.6 Hz, 1H), 8.91 (d, J = 7.6 Hz, 1H), 8.23 (s, 1H),8.03-7.97 (m, 1H), 7.83-7.80 (m, 2H), 7.64 (dd, J = 9.2, 2.4 Hz, 1H),7.55 (t, J = 8.1 Hz, 1H), 7.32 (t, J = 74.0 Hz, 1H), 7.08 (d, J = 7.4Hz, 1H), 5.02-4.97 (m, 1H), 1.39 (d, J = 6.0 Hz, 6H). DMSO 423.0 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 70

HCl 408.86 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.61 (s, 1H), 9.48 (s, 1H),9.05 (d, J = 7.2 Hz, 1H), 8.93 (d, J = 5.2 Hz, 1H), 8.19-8.15 (m, 2H),8.01-7.92 (m, 3H), 7.63-7.53 (m, 2H), 5.01-4.94 (m, 1H), 1.39 (d, J =6.0 Hz, 6H). DMSO  409.1, 411.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C,G1 71

HCl 425.31 ¹H NMR (400 MHz, DMSO-d₆): δ 9.92 (s, 1H), 9.52 (d, J = 1.2Hz, 1H), 8.70-8.66 (m, 2H), 8.17 (d, J = 1.6 Hz, 2H), 7.98 (d, J = 2.4Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.60-7.56 (m, 2H), 7.39 (t, J = 1.8Hz, 1H), 4.94-4.88 (m, 1H), 1.39 (d, J = 6.0 Hz, 6H). DMSO  424.9, 426.9(M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 72

HCl 392.4 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.28 (s, 1H), 9.49 (d, J = 1.2Hz, 1H), 8.93 (d, J = 8.0 Hz, 1H), 8.86-8.84 (m, 1H), 8.10-8.05 (m, 2H),7.93-7.85 (m, 2H), 7.71-7.69 (m, 2H), 7.61-7.52 (m, 1H), 4.97-4.91 (m,1H), 1.39 (d, J = 6.0 Hz, 6H). DMSO 393.0 (M + 1) Method B (NH4HCO3) 95Meth-od C, G1 73

HCl 385.42 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.03 (s, 1H), 9.53 (d, J = 1.2Hz, 1H), 9.10 (d, J = 3.4 Hz, 1H), 8.93-8.90 (m, 2H), 8.49 (s, 1H),8.01-7.91 (m, 4H), 7.69 (t, J = 7.6 Hz, 1H), 7.59-7.54 (m, 2H), 7.24 (t,J = 7.6 Hz, 1H), 4.21 (q, J = 6.8 Hz, 2H), 1.46 (t, J = 6.9 Hz, 3H).DMSO 386.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 74

HCl 367.4 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.35 (s, 1H), 9.49 (s, 1H), 8.95(d, J = 7.6 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 8.37 (s, 1H), 8.28 (d, J= 7.6 Hz, 1H), 8.08 (s, 1H), 7.94-7.85 (m, 2H), 7.73-7.60 (m, 3H), 4.28(q, J = 6.8 Hz, 2H), 1.46 (t, J = 6.8 Hz, 3H). DMSO 368.1 (M + 1) MethodB (NH4HCO3) 95 Meth-od C, G1 75

HCl 394.83 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 1H), 9.44 (s, 1H),8.99 (d, J = 8.4 Hz, 1H), 8.91 (d, J = 4.4 Hz, 1H), 8.17 (d, J = 3.2 Hz,2H), 7.59-7.50 (m, 2H), 4.26 (q, J = 8.8 Hz, 2H), 1.44 (t, J =- 6.8 Hz,3H). DMSO 395.1 397.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 76

HCl 411.28 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.48 (s, 1H), 9.47 (s, 1H),9.02 (d, J = 7.6 Hz, 1H), 8.91 (d, J = 4.4 Hz, 1H), 8.28 (d, J = 1.6 Hz,1H), 8.13 (s, 1H), 8.01-7.91 (m, 3H), 7.72 (d, J = 8.8 Hz, 1H),7.59-7.57 (m, 1H), 4.26 (q, J = 6.8 Hz, 2H), 1.44 (t, J = 6.8 Hz, 3H).DMSO 411.0 413.0 415.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 77

HCl 411.28 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.23 (s, 1H), 9.48 (s, 1H),8.93 (d, J = 8.0 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 8.14 (s, 2H), 8.05(d, J = 1.6 Hz, 1H), 7.92-7.85 (m, 2H), 7.61 (dd, J = 9.1, 1.8 Hz, 1H),7.41 (s, 1H), 4.26 (q, J = 6.8 Hz, 2H), 1.45 (t, J = 6.8 Hz, 3H). DMSO411.0 413.1 415.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 78

HCl 378.37 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.39 (s, 1H), 9.49 (s, 1H),8.98 (d, J = 8.0 Hz, 1H), 8.88 (d, J = 4.8 Hz, 1H), 8.11-8.05 (m, 2H),7.95-7.91 (m, 2H), 7.72-7.52 (m, 3H), 4.28 (q, J = 6.8 Hz, 2H), 1.45 (t,J = 6.8 Hz, 3H). DMSO 379.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G179

HCl 429.47 ¹H-NMR (400 MHz, DMSO-d₆): δ 12.99 (s, 1H), 9.59 (d, J = 1.6Hz, 1H), 9.14 (d, J = 7.6 Hz, 1H), 8.75-8.69 (m, 2H), 8.48 (s, 1H),7.99-7.96 (m, 2H), 7.90 (d, J = 8.8 Hz, 1H), 7.76-7.72 (m, 1H),7.61-7.56 (m, 3H), 7.22-7.19 (m, 1H), 4.24 (t, J = 6.0 Hz, 2H), 3.56 (t,J = 6.0 Hz, 2H), 3.28 (s, 3H), 2.11-2.04 (m, 2H). DMSO 430.1 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 80

HCl 380.80 ¹H-NMR (400 MHz, DMSO-d₆): δ 11.67 (s, 1H), 9.18 (d, J = 2.0Hz, 1H), 8.90 (d, J = 8.4 Hz, 1H), 8.66 (dd, J = 8.8, 2.4 Hz, 1H), 8.35(d, J = 8.4 Hz, 1H), 8.14-8.08 (m, 2H), 7.90-7.81 (m, 2H), 7.62 (t, J =9.2 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 3.98 (s, 3H). DMSO  380.9, 382.9(M + 1) Method A (TFA) 95 Meth-od C, G1 81

HCl 394.79 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.81 (s, 1H), 9.49 (d, J = 1.2Hz, 1H), 9.28 (d, J = 0.8 Hz, 1H), 9.15 (d, J = 8.0 Hz, 1H), 9.02 (d, J= 5.2 Hz, 1H), 8.37- 8.34 (m, 1H), 8.12-8.09 (m, 2H), 8.01 (d, J = 8.4Hz, 1H), 7.95-7.91 (m, 1H), 7.53 (t, J = 9.0 Hz, 1H). DMSO  395.0, 397.0(M + 1) Method B (NH₄HCO₃) 95 Meth-od C, G1 82

385.39 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.63 (d, J = 1.6 Hz, 1H), 9.13 (s,1H), 8.80-8.75 (m, 2H), 8.21 (d, J = 9.2 Hz, 1H), 7.97-7.94 (m, 1H),7.82 (dd, J = 9.2, 2.8 Hz, 1H), 7.73 (dd, J = 9.2, 2.4 Hz, 1H),7.64-7.61 (m, 1H), 7.38-7.32 (m, 2H), 4.18 (q, J = 6.8 Hz, 2H), 3.19 (t,J = 7.0 Hz, 3H). DMSO 386.1 (M + 1) Method B (NH₄HCO₃) 95 Meth-od C, G1083

HCl 426.39 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.43 (s, 1H), 9.49 (d, J = 1.6Hz, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.89 (dd, J = 9.2, 1.6 Hz, 1H), 8.13(d, J = 2.4 Hz, 1H), 8.05 (s, 1H), 7.97-7.89 (m, 3H), 7.65-7.61 (m, 2H),7.23 (d, J = 8.4 Hz, 1H), 4.29 (q, J = 6.8 Hz, 2H), 1.46 (t, J = 7.2 Hz,3H). DMSO 427.1 (M + 1) Method B (NH₄HCO₃) 95 Meth-od C, G1 84

426.47 ¹H-NMR (400 MHz, DMSO-d₆): δ 12.00 (s, 1H), 9.55 (s, 1H), 9.12(d, J = 8.0 Hz, 1H), 8.94 (d, J = 4.8 Hz, 1H), 8.84 (d, J = 8.4 Hz, 1H),8.11-8.09 (m, 1H), 8.02-7.99 (m, 1H), 7.96 (d, J = 9.2 Hz, 1H),7.82-7.11 (m, 1H), 7.65 (s, 1H); 7.62-7.59 (m, 1H), 7.30 (t, J = 7.2,Hz, 1H), 5.06-5.03 (m, 1H), 2.15-2.09 (m, 2H), 1.86-1.74 (m, 4H),1.68-1.65 (m, 2H) DMSO 427.0 (M + 1) Method B (NH₄HCO₃) 95 Meth-od C, G185

375.81 1H-NMR (400 MHz, DMSO-d6): δ 13.09 (s, 1H), 9.58 (s, 1H), 9.12(d, J = 8.4 Hz, 1H), 8.94 (d, J = 4.4 Hz, 1H), 8.88 (d, J = 8.4 Hz, 1H),8.50 (s, 1H), 8.25 (s, 1H), 8.01-7.96 (m, 5H), 7.71 (t, J = 8.0 Hz, 1H),7.27 (t, J = 8.0 Hz, 1H). DMSO  376.0, 378.0 (M + 1) 397.9 (M + 23)188.4 (M/2 + 1) Method A (TFA) 95 Meth-od C, G1 86

398.79 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.10 (s, 1H), 9.54 (s, 1H), 8.78(s, 1H), 8.71-8.67 (m, 2H), 7.96 (s, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.82(d, J = 8.0 Hz, 1H), 7.56-7.51 (m, 2H), 7.30 (t, J = 74.0 Hz, 1H), 7.01(dd, J = 2.0, 8.0 Hz, 1H). DMSO  399.0, 401.0 (M + 1)  199.9, 200.8(M/2 + 1) Method A (TFA) 95 Meth-od C, G1 87

443.7 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.09 (s, 1H), 9.39 (s, 1H), 8.93 (d,J = 8.4 Hz, 1H), 8.90 (d, J = 5.6 Hz, 1H), 8.62 (d, J = 1.6 Hz, 1H),8.11 (dd, J = 6.8, 2.4 Hz, 1H), 7.95-7.91 (m, 1H), 7.89-7.85 (m, 1H),7.80 (s, 1H), 7.45 (t, J = 8.8 Hz, 1H), 2.66 (s, 3H). DMSO  443.0, 445.0, 447.0 (M + 1) Method B (NH₄HCO₃) 98 Meth-od C, G1 88

401.42 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.19 (s, 1H), 9.43 (d, J = 8.0 Hz,1H), 8.53 (s, 1H), 8.31 (dd, J = 4.8, 1.6 Hz, 1H), 8.26 (dd, J = 1.6,7.2 Hz, 1H), 8.03 (s, 1H), 7.96-7.89 (m, 1H), 7.86 (d, J = 9.2 Hz, 1H),7,65-7.54 (m, 3H), 7.18-7.12 (m, 2H), 4.02 (s, 3H), 3.98 (s, 3H). DMSO402.1 (M + 1) Method B (NH₄HCO₃) 95 Meth-od C, G1 89

410.83 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.79 (s, 1H), 8.52 (dd, J = 2.4, 7.2Hz, 1H), 8.28 (dd, J = 5.6, 2.4 Hz, 1H), 8.12 (dd, J = 2.4, 5.2 Hz, 1H),7.98-7.94 (m, 2H), 7.82 (d, J = 9.2 Hz, 1H), 7.56 (dd, J = 9.2, 2.8 Hz,1H), 7.47 (t, J = 9.2 Hz, 1H), 7.14-7.11 (m, 1H), 4.00 (s, 3H), 3.9 (s,3H). DMSO  411.1, 413.1 (M + 1) Method B (NH₄HCO₃) 95 Meth-od C, G1 90

415.44 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.03 (s, 1H), 9.21 (d, J = 2.2 Hz,1H), 9.16 (d, J = 7.9 Hz, 1H), 8.67 (dd, J = 8.7, 2.4 Hz, 1H), 8.50 (s,1H), 8.02 (s, 1H), 7.99-7.93 (m, 1H), 7.84 (d, J = 8.9 Hz, 1H),7.78-7.72 (m, 1H), 7.56 (dd, J = 11.2, 2.1 Hz, 2H), 7.19 (t, J = 7.2 Hz,1H), 6.99 (d, J = 8.8 Hz, 1H), 4.24 (q, J = 6.9 Hz, 2H), 3.96 (s, 3H),1.46 (t, J = 6.9 Hz, 3H). DMSO 416.1 (M + 1) Method B (NH₄HCO₃) 95Meth-od D, G1 91

HCl 405.84 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.28 (s, 1H), 9.55 (d, J = 1.7Hz, 1H), 9.31 (d, J = 2.1 Hz, 1H), 8.90 (d, J = 8.3 Hz, 1H), 8.83 (dd, J= 5.0, 1.4 Hz, 1H), 8.58 (s, 1H), 8.12 (s, 1H), 8.01 (d, J = 8.6 Hz,1H), 7.93 (d, J = 9.1 Hz, 1H), 7.82 (dd, J = 7.9, 5.0 Hz, 1H), 7.63 (dd,J = 9.1, 2.6 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.30 (dd, J = 8.5, 2.2Hz, 1H), 3.98 (s, 3H). DMSO  406.0, 408.0 (M + 1) Method A (TFA) 95Meth-od C, G1 92

429.47 ¹H-NMR (400 MHz, DMSO-d₆): δ 12.99 (s, 1H), 9.21 (d, J = 2.0 Hz,1H), 9.14 (d, J = 8.4 Hz, 1H), 8.67 (dd, J = 8.7, 2.3 Hz, 1H), 8.49 (s,1H), 8.05-7.90 (m, 2H), 7.85 (d, J = 9.0 Hz, 1H), 7.75 (t, J = 7.2 Hz,1H), 7.67-7.47 (m, 2H), 7.20 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 8.8 Hz,1H), 4.15 (t, J = 6.3 Hz, 2H), 3.96 (s, 3H), 1.07 (t, J = 7.4 Hz, 3H),1.86 (dd, J = 14.0, 6.7 Hz, 2H). DMSO 430.1 (M + 1) Method B (NH₄HCO₃)95 Meth-od C, G1 93

HCl 389.38 ¹H-NMR (400 MHz, DMSO-d₆): δ 11.34 (s, 1H), 9.52 (d, J = 1.7Hz, 1H), 8.99 (d, J = 7.8 Hz, 1H), 8.85 (dd, J = 5.2, 1.3 Hz, 1H), 8.22(d, J = 8.1 Hz, 1H), 8.11-8.00 (m, 2H), 7.95 (d, J = 9.1 Hz, 1H), 7.87(dd, J = 7.9, 5.3 Hz, 1H), 7.77-7.59 (m, 3H), 7.27-7.16 (m, 1H), 3.99(s, 3H). DMSO 390.1 (M + 1) Method B (NH₄HCO₃) 95 Meth-od C, G1 94

436.29 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.62 (s, 1H), 9.17 (s, 1H), 8.77 (d,J = 8.0 Hz, 1H), 8.76 (d, J = 4.0 Hz, 1H), 8.26-8.07 (m, 3H), 7.83 (dd,J = 9.1, 2.5 Hz, 1H), 7.63 (dd, J = 7.5, 5.0 Hz, 1H), 7.36 (d, J = 2.4Hz, 1H), 4.18 (q, J = 6.8 Hz, 2H), 1.39 (t, J = 6.9 Hz, 3H). DMSO 436.1, 438.0 (M + 1) Method B (NH₄HCO₃) 95 Meth-od C, G1 95

405.84 ¹H-NMR (400 MHz, DMSO-d₆): δ 12.93 (s, 1H), 9.58 (s, 1H), 9.16(d, J = 9.0 Hz, 1H), 8.70-8.74 (m, 2H), 8.59 (s, 1H), 8.13 (s, 1H), 8.05(d, J = 2.3 Hz, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.82 (dd, J = 8.9, 2.1Hz, 1H), 7.65-7.49 (m, 3H), 3.98 (s, 3H). DMSO  406.1, 408.0 (M + 1)Method B (NH₄HCO₃) 95 Meth-od C, G1 96

429.67 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.45 (s, 1H), 9.47 (s, 1H),9.02-8.92 (m, 3H), 8.18-8.16 (m, 1H), 8.06-8.04 (m, 1H), 7.96-7.84 (m,3H), 7.54-7.50 (m, 1H). DMSO  429.9,  431.0, 433.0 (M + 1) Method B(NH₄HCO₃) 95 Meth-od C, G1 97

398.79 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.25 (s, 1H), 9.58 (s, 1H),8.85-8.76 (m, 2H), 8.60 (d, J = 7.2 Hz, 1H), 8.12-8.10 (m, 1H), 7.92 (s,1H), 7.83-7.80 (m, 1H), 7.71-7.64 (m, 2H), 7.56-7.52 (m, 1H), 7.30 (t, J= 74.0 Hz, 1H), 7.05-7.03 (m, 1H). DMSO  399.0, 401.0 (M + 1) Method B(NH₄HCO₃) 95 Meth-od C, G1 98

385.22 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.47 (s, 1H), 9.50 (s, 1H), 9.04(d, J = 8.0 Hz, 1H), 8.93 (d, J = 5.2 Hz, 2H), 8.64 (d, J = 8.8 Hz, 1H),8.20-8.18 (m, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.97-7.92 (m, 2H),7.68-7.64 (m, 1H), 7.53 (t, J = 9.2 Hz, 1H). DMSO  385.0, 386.9 (M + 1)Method B (NH₄HCO₃) 95 Meth-od C, G1 99

401.66 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.42 (s, 1H), 9.55 (d, J = 1.6 Hz,1H), 8.96 (d, J = 4.0 Hz, 1H), 8.88-8.87 (m, 1H), 8.61 (d, J = 7.6 Hz,1H), 8.32 (d, J = 2.4 Hz, 1H), 8.14-8.12 (m, 1H), 7.99-7.95 (m, 1H),7.88 (dd, J = 8.0, 5.2 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.70-7.67 (m,1H). DMSO  400.9,  402.9, 404.9 (M + 1) Method B (NH₄HCO₃) 95 Meth-od C,G1 100

368.77 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.47 (s, 1H), 9.51 (d, J = 1.2 Hz,1H), 9.04 (d, J = 3.0 Hz, 1H), 8.92 (d, J = 5.6 Hz, 1H), 8.65 (d, J =8.0 Hz, 1H), 8.11-8.05 (m, 2H), 7.97 (dd, J = 8.0, 4.0 Hz, 1H),7.75-7.73 (m, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.58-7.51 (m, 1H). DMSO369.0, 371.0 (M + 1) Method B (NH₄HCO₃) 95 Meth-od C, G1 101

375.09 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.18 (s, 1H), 9.61 (s, 1H), 9.02(d, J = 8.4 Hz, 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.83 (d, J = 4.0 Hz, 1H),8.52 (s, 1H), 8.16-8.08 (m, 2H), 7.98-7.94 (m, 2H), 7.80-7.67 (m, 3H),7.26 (t, J = 7.6 Hz, 1H). DMSO  376.0, 378.0 (M + 1) Method B (NH₄HCO₃)95 Meth-od C, G1 102

401.68 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.47 (s, 1H), 9.49 (d, J = 2.0 Hz,1H), 9.00-8.98 (m, 1H), 8.91 (dd, J = 5.2, 1.6 Hz, 1H), 8.64-8.62 (m,1H), 8.12-8.09 (m, 3H), 7.94 (dd, J = 8.0, 5.2 Hz, 1H), 7.67 (t, J = 8.0Hz, 1H), 7.41 (t, J = 2.0 Hz, 1H). DMSO  400.9,  402.9, 404.9 (M + 1)Method B (NH₄HCO₃) 95 Meth-od C, G1 103

434.77 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.17 (d, J = 1.2 Hz, 1H), 9.51 (s,1H), 8.71-8.62 (m, 3H), 8.25-8.22 (m, 1H), 8.04-8.00 (m, 1H), 7.92-7.87(m, 2H), 7.58-7.53 (m, 2H). DMSO  435.1, 437.1 (M + 1) Method B(NH₄HCO₃) 95 Meth-od C, G1 104

448.35 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.16 (s, 1H), 9.55 (d, J = 1.2 Hz,1H), 8.72-8.68 (m, 3H), 8.05 (d, J = 9.2 Hz, 1H), 7.92-7.95 (m, 2H),7.80 (dd, J = 8.0, 1.2 Hz, 1H), 7.57-7.53 (m, 2H), 7.31 (t, J = 74.4 Hz,1H), 7.03 (dd, J = 8.0, 1.2 Hz, 1H). DMSO 449.1 (M + 1) Method B(NH₄HCO₃) 95 Meth-od C, G1 105

425.36 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.24 (s, 1H), 9.59 (s, 1H), 9.05(d, J = 8.0 Hz, 1H), 8.74-8.73 (m, 2H), 8.54 (s, 1H), 8.10-7.91 (m, 5H),7.77-7.73 (m, 1H), 7.61-7.58 (m, 1H), 7.26 (t, J = 7.6 Hz, 1H DMSO 426.1(M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 106

448.35 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.23 (s, 1H), 9.55 (d, J = 1.6 Hz,1H), 8.76 (d, J = 9.1 Hz, 1H), 8.74-8.67 (m, 2H), 7.94 (t, J = 2.0 Hz,1H), 7.82-7.78 (m, J = 10.3 Hz, 2H), 7.68 (dd, J = 9.0, 1.8 Hz, 1H),7.59-7.50 (m, 2H), 7.30 (t, J = 74.0 Hz, 1H), 7.03 (dd, J = 8.2, 2.2 Hz,1H). DMSO 449.0 (M + 1) 225.0 (M/2 + 1) Method A (TFA) 95 Meth-od C, G1107

425.36 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.17 (s, 1H), 9.59 (s, 1H), 9.04(d, J = 8.0 Hz, 1H), 8.74-8.70 (m, 2H), 8.51 (s, 1H), 8.30 (d, J = 9.0Hz, 1H), 8.02-7.90 (m, 2H), 7.86-7.69 (m, 3H), 7.65-7.56 (m, 1H), 7.25(t, J = 9.8 Hz, 1H). DMSO 426.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C,G1 108

434.77 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.26 (s, 1H), 9.52 (s, 1H),8.81-8.59 (m, 3H), 8.24 (dd, J = 6.9, 2.5 Hz, 1H), 7.89-7.52 (m, 1H),7.79 (s, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.65-7.50 (m, 2H). DMSO  435.0,437.0 (M + 1) 218.1 (M/2 + 1) Method A (TFA) 95 Meth-od C, G1 109

455.39 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.35 (s, 1H), 9.58 (s, 1H), 9.27(s, 1H), 8.83-8.70 (m, 2H), 8.62 (s, 1H), 8.18 (s, 1H), 8.11 (d, J = 8.8Hz, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.68-7.58 (m, 2H), 7.54 (d, J = 2.5Hz, 1H), 7.19 (dd, J = 8.4, 2.17 Hz, 1H), 3.98 (s, 3H). DMSO 456.0(M + 1) 228.5 (M/2 + 1) Method A (TFA) 95 Meth-od C, J1 110

425.48 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.08 (s, 1H), 9.59 (s, 1H), 9.07(d, J = 7.6 Hz, 1H), 9.02 (d, J = 8.0 Hz, 1H), 8.89 (d, J = 4.0 Hz, 1H),8.50 (s, 1H), 7.92-7.99 (m, 4H), 7.73 (t, J = 7.6 Hz, 1H), 7.59-7.60 (m,2H), 7.25 (t, J = 7.6 Hz, 1H), 2.12-2.15 (m, 2H), 5.02-5.03 (m, 1H),1.67-1.86 (m, 6H). DMSO 426.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C,G1 111

448.46 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.26 (s, 1H), 9.50 (d, J = 1.6 Hz,1H), 8.95 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 4.4 Hz, 1H), 8.08 (s, 1H),7.94 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 9.6 Hz, 2H), 7.79 (d, J = 8.8 Hz,1H), 7.60-7.63 (m, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.31 (t, J = 74.0 Hz,1H), 7.05 (d, J = 8.4 Hz, 1H), 5.14 (s, 1H), 2.03-2.09 (m, 2H),1.61-1.81 (m, 6H). DMSO 449.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C,G1 112

434.89 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.47 (s, 1H), 9.47 (s, 1H), 8.97(d, J = 7.6 Hz, 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.16-8.19 (m, 1H),7.53-7.61 (m, 2H), 8.10 (s, 1H), 7.90-7.96 (m, 3H), 5.15 (s, 1H),2.09-2.10 (m, 2H), 1.67-1.78 (m, 6H). DMSO  435.0, 437.0 (M + 1) MethodB (NH4HCO3) 95 Meth-od C, G1 113

451.35 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.23 (s, 1H), 9.49 (s, 1H), 8.85(d, J = 7.6 Hz, 1H), 8.80 (d, J = 4.0 Hz, 1H), 8.32 (s, 1H), 8.03 (s,1H), 7.97-7.99 (m, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.77-7.79 (m, 1H),7.75 (d, J = 8.3 Hz, 1H), 7.55-7.58 (m, 1H), 5.13 (s, 1H), 2.08 (d, J =8.4 Hz, 2H), 1.79 (d, J = 9.6 Hz, 4H). DMSO  451.0, 453.0 (M + 1) MethodB (NH4HCO3) 95 Meth-od C, G1 114

418.44 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.24 (s, 1H), 9.49 (s, 1H), 8.92(d, J = 8.0 Hz, 1H), 8.40 (d, J = 6.4 Hz, 1H), 8.04-8.11 (m, 2H), 7.92(d, J = 9.2 Hz, 1H), 7.84-7.91 (m, 1H), 7.69-7.71 (m, 1H), 7.52-7.61 (m,2H), 5.13 (s, 1H), 2.06-2.11 (m, 2H), 1.65-1.81 (m, 6H). DMSO 419.0(M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 115

407.47 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 1H), 9.45 (s, 1H), 8.98(d, J = 6.8 Hz, 1H), 8.89 (d, J = 6.0 Hz, 1H), 8.37 (s, 1H), 8.32 (d, J= 6.8 Hz, 1H), 8.18 (s, 1H), 7.93 (t, J = 9.2 Hz, 2H), 7.70 (t, J = 7.2Hz, 2H), 7.56 (d, J = 8.8 Hz, 1H), 5.18 (s, 1H), 2.09 (s, 2H), 1.77 (m,4H), 1.66 (m, 2H). DMSO 408.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C,G1 116

401.68 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.81 (s, 1H), 9.47 (s, 1H), 8.71 (d,J = 6.4 Hz, 1H), 8.62 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 7.88 (t, J =7.2 Hz, 3H), 7.75-7.73 (m, 2H), 7.57-7.56 (m, 1H). DMSO  401.0, 403.0405.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 117

368.77 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.74 (s, 1H), 9.45 (d, J = 1.2 Hz,1H), 8.70 (dd, J = 4.4, 1.6 Hz, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.04-8.00(m, 1H), 7.88-7.85 (m, 2H), 7.74 (dd, J = 8.4, 1.6 Hz, 1H), 7.85-7.63(m, 1H), 7.57-7.56 (m, 2H). DMSO  369.1, 371.1 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 118

436.34 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.33 (s, 1H), 8.87-8.20 (m, 2H),8.27 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.90-7.72 (m, 3H),7.39-7.36 (m, 2H), 3.44 (brs, 4H), 2.05 (brs, 4H). DMSO  435.9,  437.9,439.8 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 119

403.43 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.38 (s, 1H), 9.43 (d, J = 1.2 Hz,1H), 8.85-8.80 (m, 2H), 8.07-8.05 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H),7.81 (t, J = 6.8 Hz, 1H), 7.69-7.67 (m, 1H), 7.58-7.83 (m, 1H),7.43-7.41 (m, 2H), 3.45 (brs, 4H), 2.06 (brs, 4H). DMSO 403.9 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 120

368.77 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.28 (s, 1H), 9.49 (s, 1H),8.77-8.87 (m, 3H), 8.06-8.12 (m, 1H), 7.90-7.95 (m, 2H), 7.78-7.81 (m,1H), 7.57-7.73 (m, 1H), 7.53 (dd, J = 19.6 Hz, 9.2 Hz, 1H). DMSO  369.0,371.1 (M + 1) Method A (TFA) 95 Meth-od C, G1 121

401.68 1H-NMR (400 MHz, DMSO-d6): δ 10.37 (s, 1H), 9.52 (s, 1H), 8.95(d, J = 3.2 Hz, 1H), 8.87 (m, 1H), 8.81 (s, 1H), 8.32 (d, J = 2.0 Hz,1H), 7.95-7.99 (m, 3H), 7.87-7.89 (m, 1H), 7.72 (d, J = 8.8 Hz, 1H).DMSO  401.0,  403.0, 405.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1122

385.22 1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 9.50 (s, 1H), 8.69(s, 2H), 8.64 (d, J = 8.0 Hz, 1H), 8.26 (dd, J = 10.6 Hz, 1.8 Hz, 1H),7.89-7.90 (m, 3H), 7.51-7.57 (m, 2H). DMSO  385.0, 387.0 (M + 1) MethodB (NH4HCO3) 95 Meth-od C, G1 123

357.8 1H-NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 9.52 (s, 1H),8.67-8.76 (m, 3H), 8.44 (s, 1H), 8.27 (m, 1H), 7.96 (s, 2H), 7.66-7.69(m, 2H), 7.57-7.59 (m, 1H). DMSO 358.0 (M + 1) Method A (TFA) 95 Meth-odC, G1 124

411.86 1H-NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 9.54 (s, 1H), 9.08(d, J = 8.4 Hz, 1H), 8.94-8.90 (m, 2H), 8.15 (d, J = 8.4 Hz, 2H),8.00-7.93 (m, 5H), 7.39 (s, 2H). DMSO  412.0, 414.0 (M + 1) Method A(TFA) 95 Meth-od C, G1 125

411.86 1H-NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 9.54 (s, 1H), 9.22(s, 1H), 8.92-8.98 (m, 2H), 8.70 (s, 1H), 8.10 (s, 1H), 8.03-8.05 (m,1H), 7.95 (s, 2H), 7.69 (s, 2H), 7.53 (s, 2H). DMSO  412.0, 414.0(M + 1) Method A (TFA) 95 Meth-od C, G1 126

364.35 1H-NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 9.47 (s, 1H), 9.02(d, J = 7.6 Hz, 1H), 8.92 (s, 1H), 8.21 (s, 1H), 8.08-8.10 (m, 1H),7.95-7.97 (m, 2H), 7.74-7.75 (m, 1H), 7.54-7.62 (m, 2H), 4.00 (s, 3H).DMSO 365.1 (M + 1), 183.1 (M/2 + 1) Method A (TFA) 95 Meth-od C, G1 127

397.26 1H-NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 9.48 (s, 1H), 9.02(d, J = 8.0 Hz, 1H), 8.91-8.92 (m, 1H), 8.28 (d, J = 2.4 Hz, 1H),8.16-8.17 (m, 1H), 7.92-8.03 (m, 3H), 7.72 (d, J = 8.8 Hz, 1H),7.58-7.61 (m, 1H), 4.00 (s, 3H). DMSO  397.0, 399.0 (M + 1), 200.1(M/2 + 1) Method A (TFA) 95 Meth-od C, G1 128

407.45 1H-NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.55 (s, 1H),8.92-8.84 (m, 2H), 8.16-8.09 (m, 3H), 7.95-7.89 (m, 3H), 7.83-7.79 (m,1H), 7.62-7.58 (m, 1H), 7.36 (s, 2H), 3.40 (s, 3H). DMSO 408.1 (M + 1)Method A (TFA) 95 Meth-od C, G1 129

362.81 1H-NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 9.51 (s, 1H),8.82-8.85 (m, 2H), 8.10- 8.11 (m, 1H), 8.05 (d, J = 2.0 Hz, 1H),7.98-7.93 (m, 2H), 7.75-7.77 (m, 1H), 7.59-7.61 (m, 1H), 7.52 (t, J =8.0 Hz, 1H), 7.27-7.28 (m, 1H), 3.99 (s, 3H). DMSO  363.0, 365.0 (M +1), 182.1 (M/2 + 1) Method A (TFA) 95 Meth-od C, G1 130

380.8 1H-NMR (300 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.50 (s, 1H), 7.7-8.79 (m, 2H), 8.19-8.24 (m, 1H), 7.86-8.00 (m, 3H), 7.52-7.70 (m, 3H),3.98 (s, 3H). DMSO  381.1, 383.1 (M + 1), 191.1 (M/2 + 1) Method A (TFA)95 Meth-od C, G1 131

371.39 1H-NMR (300 MHz, DMSO-d6): δ 13.08 (s, 1H), 9.59 (s, 1H), 9.07(d, J = 8.1 Hz, 1H), 8.96 (d, J = 8.1 Hz, 1H), 8.83 (d, J = 3.9 Hz, 1H),8.49 (s, 1H), 7.89-7.99 (m, 3H), 7.80-7.84 (m, 1H), 7.72 (t, J = 7.8 Hz,1H), 7.60-7.63 (m, 2H), 7.23 (t, J = 7.5 Hz, 1H), 3.98 (s, 3H). DMSO371.9 (M + 1) Method A (TFA3) 95 Meth-od C, G1 132

362.81 1H-NMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 9.28 (s, 1H), 8.69(d, J = 4.0 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 2.8 Hz, 1H),7.87 (d, J = 9.2 Hz, 1H), 7.68-7.70 (m, 2H), 7.57-7.63 (m, 2H),7.48-7.53 (m, 1H), 7.40-7.44 (m, 1H), 3.86 (s, 3H). DMSO  363.0, 365.1(M + 1), 182.1 (M/2 + 1) Method A (TFA) 95 Meth-od C, G1 133

348.35 1H-NMR (400 MHz, DMSO-d6): δ 9.46 (s, 1H), 9.11 (s, 1H),8.79-8.76 (m, 2H), 8.00-7.94 (m, 1H), 7.83-7.73 (m, 3H), 7.62-7.48 (m,3H), 3.00 (s, 3H). DMSO 349.1 (M + 1), 175.1 (M/2 + 1) Method A (TFA) 95Meth-od C, G1 134

381.26 1H-NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 9.13 (s, 1H),8.75-8.77 (m, 2H), 8.18 (s, 1H), 7.72-7.85 (m, 5H), 7.49-7.50 (m, 1H),3.00 (s, 3H). DMSO  381.0,  383.0, 385.0 (M + 1) Method A (TFA) 95Meth-od C, G1 135

364.8 1H-NMR (400 MHz, DMSO-d6): δ 9.43 (m, 2H), 8.94-8.89 (m, 2H),8.08- 8.06 (m, 1H), 7.92-7.81 (m, 4H), 7.57-7.53 (m, 2H), 3.03 (s, 3H).DMSO  365.0, 367.0 (M + 1), 183.1 (M/2 + 1) Method A (TFA) 95 Meth-od C,G1 136

337.38 1H-NMR (400 MHz, DMSO-d6): δ 9.52-9.44 (m, 2H), 8.98 (d, J = 8.0Hz, 1H), 8.92 (d, J = 4.4 Hz, 1H), 8.36-8.19 (m, 2H), 8.02-7.84 (m, 3H),7.73-7.69 (m, 2H), 7.55 (d, J = 6.8 Hz, 1H), 3.04 (s, 3H). DMSO 338.1(M + 1), 169.6 (M/2 + 1) Method A (TFA) 95 Meth-od C, G1 137

364.35 1H-NMR (400 MHz, DMSO-d6): δ 9.97 (s, 1H), 9.51 (s, 1H),8.69-8.66 (m, 2H), 8.16-8.08 (m, 2H), 7.75-7.73 (m, 1H), 7.61-7.53 (m,3H), 7.40 (d. J = 7.6 Hz, 1H), 4.01 (s, 3H). DMSO 183.1 (M/2 + 1) 365.1(M + 1) Method A (TFA) 95 Meth-od C, G1 138

397.26 1H-NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 9.53 (s, 1H),8.67-8.70 (m, 2H), 8.41 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H),7.95-7.99 (m, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.56-7.63 (m, 2H), 7.42 (d,J = 8.4 Hz, 1H), 4.02 (s, 3H). DMSO  397.0, 399.0 (M + 1) Method A (TFA)95 Meth-od C, G1 139

380.8 1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.48 (s, 1H), 8.99 (d,J = 8.0 Hz, 1H), 8.89 (d, J =4.8 Hz, 1H), 8.15-8.22 (m, 2H), 7.92-7.95(m, 2H), 7.62 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.8 Hz, 1H), 7.43 (d, J= 8.0 Hz, 1H), 4.02 (s, 3H). DMSO 191.1 (M/2 + 1)  381.1, 383.1 (M + 1)Method A (TFA) 95 Meth-od C, G1 140

401.68 1H-NMR (400 MHz, DMSO-d6): δ 10.11 (s, 1H), 8.50 (m, 1H),8.63-8.70 (m, 3H), 8.14 (d, J = 2.0 Hz, 2H), 7.92 (m, 2H), 7.57 (m, 1H),7.38 (t, J = 1.6 Hz, 1H). DMSO  401.0, 403.0 (M + 1) Method B (NH4HCO3)95 Meth-od C, G1 141

348.35 1H-NMR (400 MHz, DMSO-d6): δ 9.46 (s, 1H), 9.11 (s, 1H),8.76-8.70 (m, 2H), 7.95-7.99 (m, 1H), 7.78-7.60 (m, 3H), 7.54-7.44 (m,3H), 3.00 (s, 3H). DMSO 175.1 (M/2 + 1) 349.1 (M + 1) Method A (TFA) 95Meth-od C, G1 142

397.26 1H-NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 8.39 (s, 1H), 8.83(s, 2H), 8.03-8.12 (m, 3H), 7.79-7.81 (m, 2H), 7.50-7.51 (m, 1H), 7.32(s, 1H), 3.96 (s, 3H). DMSO  397.0,  399.0, 401.0 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 143

452.34 1H-NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H), 9.51 (s, 1H),8.65-8.66 (m, 2H), 8.34 -8.35 (m, 1H), 7.95-7.96 (m, 1H), 7.72- 7.80 (m,4H), 7.54 (m, 1H), 3.84 (m, 4H), 3.56 (m, 4H). DMSO  452.1, 454.0(M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 144

435.88 1H-NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1H), 9.49 (s, 1H),8.62-8.65 (m, 2H), 8.21-8.23 (m, 1H), 7.89-7.91 (m, 1H), 7.78-7.81 (m,1H), 7.72-7.73 (m, 2H), 7.51-7.54 (m, 2H), 3.84 (t, J = 4.0 Hz, 4H),3.36 (m, 4H). DMSO  436.1, 438.1 (M + 1) Method B (NH4HCO3) 95 Meth-odC, G1 145

419.43 1H-NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 9.45 (s, 1H),8.83-8.90 (m, 2H), 8.06-8.08 (m, 1H), 7.70-7.93 (m, 5H), 7.56 (dd, J =19.6, 9.6 Hz, 1H), 3.82-3.83 (m, 4H), 3.39-3.41 (m, 4H). DMSO 420.1(M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 146

408.46 1H-NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 9.44 (s, 1H), 8.90(d, J = 8.0 Hz, 1H), 8.84 (d, J = 4.4 Hz, 1H), 8.34 (s, 1H), 8.27 (d, J= 7.2 Hz, 1H), 7.67- 7.92 (m, 6H), 3.82-3.83 (m, 4H), 3.39-3.40 (m, 4H).DMSO 409.2 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 147

452.34 1H-NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.42 (s, 1H),8.85-8.87 (m, 2H), 8.11 (s, 2H), 7.73-7.88 (m, 4H), 7.38 (s, 1H),3.82-3.83 (m, 4H), 3.39-3.40 (m, 4H). DMSO  452.1,  454.1, 456.1 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 148

426.47 1H-NMR (400 MHz, DMSO-d6): δ 12.93 (s, 1H), 9.57 (m, 1H), 9.12(d, J = 8.4 Hz, 1H), 8.68-8.72 (m, 2H), 8.56 (s, 1H), 8.02 (d, J = 6.8Hz, 1H), 7.96 (s, 1H), 7.72-7.84 (m, 3H), 7.56-7.57 (m, 1H), 7.40 (m,1H), 7.19 (t, J = 8.0 Hz, 1H), 3.84 (t, J = 4.4 Hz, 4H), 3.35 (t, J =4.4 Hz, 4H). DMSO 427.2 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 149

393.84 1H-NMR (400 MHz, DMSO-d6): δ 9.71 (s, 1H), 9.48 (s, 1H),8.62-8.63 (m, 2H), 8.23 (m, 1H), 7.92 (m, 1H), 7.77 (d, J = 9.6 Hz, 1H),7.51-7.56 (m, 3H), 7.42 (m, 1H), 3.12 (s, 6H). DMSO  394.1, 396.1(M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 150

377.39 1H-NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1H), 9.48 (m, 1H),8.60-8.63 (m, 2H), 8.08- 8.14 (m, 1H), 7.77 (d, J = 9.2 Hz, 1H),7.69-7.71 (m, 1H), 7.50-7.57 (m, 3H), 7.42-7.43 (m, 1H), 3.12 (s, 6H).DMSO 378.2 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 151

410.3 1H-NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1H), 9.49 (s, 1H), 8.60-8.64(m, 2H), 8.17 (s, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.51-7.53 (m, 2H), 7.37(s, 1H), 7.32 (s, 1H), 3.11 (s, 6H). DMSO  410.1,  412.0, 414.1 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 152

410.3 1H-NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 9.45 (s, 1H),8.83-8.91 (m, 2H), 8.26-8.27 (m, 1H), 7.72-7.99 (m, 4H), 7.57-7.61 (m,2H), 3.14 (s, 6H). DMSO  410.1,  412.1, 414.0 (M + 1) Method B (NH4HCO3)95 Meth-od C, G1 153

366.42 1H-NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 9.48 (s, 1H),8.55-8.64 (m, 2H), 8.41 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.79 (d, J =9.6 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.50-7.61 (m, 3H), 7.43 (m, 1H),3.12 (s, 6H). DMSO 367.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 154

435.23 1H-NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1H), 9.53 (s, 1H),8.86-8.94 (m, 3H), 8.32-8.33 (m, 1H), 8.21 (s, 1H), 7.97-8.01 (m, 2H),7.84-7.88 (m, 1H), 7.73 (d, J = 8.8 Hz, 1H). DMSO  435.1,  437.1, 439.1(M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 155

402.32 1H-NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.51-9.52 (m, 1H),8.65-8.78 (m, 3H), 8.19 (s, 1H), 8.11 (m, 1H), 7.97 (d, J = 8.0 Hz, 1H),7.71 (m, 1H), 7.55-7.59 (m, 2H). DMSO 403.1 (M + 1) Method B (NH4HCO3)95 Meth-od C, G1 156

435.23 1H-NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 9.46 (s, 1H), 8.88-8.97 (m, 3H), 8.17 (s, 1H), 8.10-8.11 (m, 2H), 7.97 (s, 1H), 7.95 (s,1H), 7.39 (s, 1H). DMSO  435.1,  437.0, 439.1 (M + 1) Method B (NH4HCO3)95 Meth-od C, G1 157

418.77 1H-NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 9.52 (s, 1H), 8.99(d, J = 8.0 Hz, 1H), 8.88-8.90 (m, 2H), 8.20-8.23 (m, 2H), 8.01 (d, J =8.0 Hz, 1H), 7.92-7.95 (m, 2H), 7.54 (t, J = 9.2 Hz, 1H). DMSO  419.1,421.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 158

409.36 1H-NMR (400 MHz, DMSO-d6): δ 13.24 (s, 1H), 9.56 (s, 1H), 9.10(d, J = 8.4 Hz, 1H), 8.96 (s, 1H), 8.87 (d, J = 8.0 Hz, 1H), 8.54 (s,1H), 8.33 (d, J = 8.8 Hz, 1H), 8.18 (s, 1H), 7.95-8.01 (m, 4H), 7.70 (t,J = 7.6 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H). DMSO 410.1 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 159

391.35 1H-NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 8.50 (s, 1H), 9.04(d, J = 8.0 Hz, 1H), 8.96 (d, J = 8.8 Hz, 2H), 8.37 (s, 1H), 8.30-8.28(m, 1H), 8.21 (s, 1H), 7.98 (d, J = 7.6 Hz, 2H), 7.68-7.69 (m, 2H). DMSO392.2 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 160

450.34 1H-NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 9.54-9.55 (m, 1H),8.82-8.84 (m, 1H), 8.67-8.73 (m, 2H), 8.16-8.21 (m, 2H), 7.93-8.00 (m,2H), 7.54-7.64 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H). DMSO 451.1 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 161

416.78 1H-NMR (400 MHz. DMSO-d6): δ 10.10 (s, 1H), 9.49 (s, 1H),8.62-8.72 (m, 3H), 8.13 (s, 1H), 7.88-7.92 (m, 3H), 7.51-7.60 (m, 2H),7.14-7.16 (m, 1H). DMSO  417.1, 419.1 (M + 1) Method B (NH4HCO3) 95Meth-od C, G1 162

375.81 1H-NMR (400 MHz, DMSO-d6): δ 13.13 (s, 1H), 9.53 (s, 1H), 9.01(d, J = 8.0 Hz, 1H), 8.68-8.72 (m, 2H), 8.50 (s, 1H), 8.10 (d, J = 8.8,1H), 7.88-7.97 (m, 3H), 7.70-7.72 (m, 2H), 7.57-7.59 (m, 1H), 7.22 (t, J= 7.6, 1H). DMSO  376.0, 378.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C,G1 163

376.8 1H-NMR (400 MHz, DMSO-d6): δ 12.07 (s, 1H), 9.56 (s, 1H), 8.84 (d,J = 8.4 Hz, 1H), 8.71-8.73 (m, 2H), 8.34 (s, 1H), 7.96-8.09 (m, 3H),7.59-7.80 (m, 2H), 7.29 (t, J = 7.2 Hz, 1H). DMSO  377.0, 379.0 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 164

394.37 1H-NMR (400 MHz, DMSO-d6): δ 9.90 (s, 1H), 9.53 (s, 1H), 8.67 (d,J = 5.2 Hz, 2H), 7.99 (d, J = 2.4 Hz, 1H), 7.94 (m, 1H), 7.87 (d, J =9.2 Hz, 1H), 7.80 (d, J = 8.4 Hz, 7.49-7.59 (m, 3H), 7.31 (t, J = 74.0Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 3.99 (s, 3H). DMSO 395.1 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 165

HCl 458.51 1H-NMR (400 MHz, DMSO-d6): δ 9.42 (s, 1H), 8.98 (d, J = 8.4Hz, 1H), 8.68-8.71 (m, 2H), 7.94 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 8.0Hz, 1H), 7.57 (t, J = 5.6 Hz, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.19 (t,J = 7.2 Hz, 1H), 4.52 (s, 2H), 4.00 (s, 3H), 3.63 (s, 2H), 2.89 (s, 6H).DMSO 459.1 (M + 1) 230.2 (M/2 + 1) Method A (TFA) 95 Meth-od C, G1 166

467.92 1H-NMR (400 MHz, DMSO-d6): δ 9.71 (s, 1H), 9.50 (d, J = 1.6 Hz,1H), 8.62-8.67 (m, 2H), 8.20 (dd, J = 6.8, 2.4 Hz, 1H), 7.86-7.89 (m,2H), 7.51-7.55 (m, 2H), 7.31 (s, 1H), 4.24 (t, J = 6.0 Hz, 2H), 3.98 (s,3H), 2.77 (t, J = 5.6 Hz, 2H), 2.29 (s, 6H). DMSO 468.1 (M + 1) 234.6(M/2 + 1) Method B (NH4HCO3) 95 Meth-od C, G1 167

HCl 428.82 1H-NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 9.50 (d, J = 1.6Hz, 1H), 8.98 (d, J = 8.4 Hz, 1H), 8.88 (dd, J = 5.2, 1.6 Hz, 1H), 8.13(d, J = 2.8 Hz, 1H), 8.00 (t, J = 2.0 Hz, 1H), 7.89-7.95 (m, 3H), 7.62(dd, J = 9.2, 3.2 Hz, 1H), 7.36 (t, J = 73.6 Hz, 1H), 7.16 (d, J = 2.0Hz, 1H), 4.01 (s, 3H). DMSO  429.1, 431.1 (M + 1) Method B (NH4HCO3) 95Meth-od C, G1 168

385.42 1H-NMR (400 MHz, DMSO-d6): δ 13.03 (s, 1H), 9.62 (d, J = 1.6 Hz,1H), 9.20 (d, J = 8.4 Hz, 1H), 8.74-8.77 (m, 1H), 8.70 (dd, J = 4.4, 1.6Hz, 1H), 8.48 (s, 1H), 7.96-7.99 (m, 2H), 7.72-7.76 (m, 1H), 7.57- 7.60(m, 1H), 7.47 (m, 1H), 7.41 (m, 1H), 7.17-7.21 (m, 1H), 3.95 (s, 3H),2.72 (s, 3H). DMSO 386.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 169

HCl 368.77 1H-NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 9.47 (s, 1H),8.86-8.93 (m, 2H), 8.54 (dd, J = 10.0, 2.8 Hz, 1H), 8.21 (dd, J = 6.8,2.4 Hz, 1H), 7.82-8.00 (m, 4H), 7.52 (t, J = 9.2 Hz, 1H). DMSO  369.0,371.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 170

HCl 400.33 1H-NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 9.53 (s, 1H),8.99 (d, J = 8.0 Hz, 1H), 8.89 (d, J = 4.0 Hz, 1H), 8.60 (dd, J = 10.4,3.2 Hz, 1H), 7.97-8.09 (m, 3H), 7.88-7.92 (m, 2H), 7.62 (t, J = 8.0 Hz,1H), 7.21 (d, J = 8.0 Hz, 1H). DMSO 401.1 (M + 1) Method B (NH4HCO3) 95Meth-od C, G1 171

359.36 1H-NMR (400 MHz, DMSO-d6): δ 13.06 (s, 1H), 9.58 (s, 1H), 9.07(d, J = 8.4 Hz, 1H), 8.72 (d, J = 5.6 Hz, 2H), 8.52 (s, 1H), 7.96-8.02(m, 3H), 7.83-7.87 (m, 2H), 7.74 (t, J = 8.0 Hz, 1H), 7.59 (t, J = 6.0Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H). DMSO 360.1 (M + 1) Method B (NH4HCO3)95 Meth-od C, G1 172

HCl 382.34 1H-NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 9.53 (d, J = 1.2Hz, 1H), 8.98 (d, J = 8.0 Hz, 1H), 8.88 (d, J = 4.4 Hz, 1H), 8.62 (dd, J= 10.0, 2.8 Hz, 1H), 8.01-8.05 (m, 1H), 7.84-7.92 (m, 4H), 7.50-7.56 (m,1H), 7.32 (t, J = 74.0 Hz, 1H), 7.03 (dd, J = 8.0, 2.0 Hz, 1H). DMSO383.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 173

348.35 1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 9.51 (s, 1H), 8.79-8.76 (m, 2H), 8.38 (s, 1H), 8.16-8.11 (m, 1H), 7.36-7.66 (m, 4H),7.59-7.50 (m, 1H), 2.57 (s, 3H). DMSO 349.1 (M + 1), 175.1 (M/2 + 1)Method A (TFA) 95 Meth-od C, G1 174

364.8 1H-NMR (300 Hz, CD3OD): δ 9.50 (d, J = 1.2 Hz, 1H), 9.14 (d, J =8.4 Hz, 1H), 8.94 (d, J = 4.8 Hz, 1H), 8.35 (s, 1H), 8.09-7.99 (m, 2H),7.93 (s, 2H), 7.78-7.73 (m, 1H), 7.39 (t, J = 9.0 Hz, 1H), 2.64 (s, 3H).CD3OD  365.1, 367.1 (M + 1) Method A (TFA) 95 Meth-od C, G1 175

381.26 1H-NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 9.51 (s, 1H),8.84-8.79 (m, 2H), 8.36-8.34 (m, 2H), 7.96 (dd, J = 8.8, 2.5 Hz, 1H),7.85-7.70 (m, 4H), 2.55 (s, 3H). DMSO  381.0, 383.0 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 176

346.81 1H-NMR (300 Hz, CD3OD): δ 9.48 (d, J = 1.2 Hz, 1H), 8.99-8.95 (m,1H), 8.82-8.80 (m, 1H), 8.30-8.29 (m, 1H), 7.90-7.81 (m, 5H), 7.52-7.46(m, 2H), 2.62 (s, 3H). DMSO  347.0, 349.1 (M + 1) Method A (TFA) 95Meth-od C, G1 177

346.81 1H-NMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 9.52 (s, 1H),8.84-8.78 (m, 2H), 8.42 (s, 1H), 8.16-8.15 (m, 1H), 7.94-7.91 (m, 1H),7.85 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.75-7.71 (m, 1H),7.50 (t, J = 8.1 Hz, 1H), 7.27-7.23 (m, 1H), 2.56 (s, 3H). DMSO  347.1,349.1 (M + 1) Method A (TFA) 95 Meth-od C, G1 178

380.37 1H-NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1H), 9.50 (d, J = 2.1 Hz,1H), 9.00 (d, J = 8.1 Hz, 1H), 8.90 (dd, J = 5.1, 1.2 Hz, 1H), 8.55 (s,1H), 8.43 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.96-7.90 (m, 2H), 7.84 (d,J = 8.1 Hz, 1H), 7.27 (t, J = 8.2 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H),2.62 (s, 3H). DMSO 381.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 179

414.81 1H-NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 9.50 (s, 1H), 9.02(d, J = 8.4 Hz, 1H), 8.92 (d, J = 5.2 Hz, 1H), 8.59 (d, J = 2.8 Hz, 1H),8.54 (s, 1H), 8.34 (dd, J = 8.6, 2.6 Hz, 1H), 7.96-7.90 (m, 2H), 7.81(d, J = 8.8 Hz, 2H), 2.56 (s, 3H). DMSO  415.1, 417.1 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 180

401.37 1H-NMR (400 MHz, DMSO-d6): δ 13.91 (s, 1H), 10.38 (s, 1H), 9.59(s, 1H), 8.79-8.76 (m, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.61 (d, J = 2.4Hz, 1H), 8.44 (s, 1H), 8.33 (dd, J = 9.0, 2.6 Hz, 1H), 8.20 (d, J = 8.8Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.81 (dd, J = 8.4, 1.2 Hz, 1H),7.60-7.57 (m, 1H), 2.58 (s, 3H). DMSO 402.0 (M + 1) Method A (TFA) 95Meth-od C, G1 181

381.26 1H-NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 9.47 (s, 1H), 8.98(d, J = 7.5 Hz, 1H), 8.91 (d, J = 4.5 Hz, 1H), 8.48 (s, 1H), 8.12 (d, J= 2.1 Hz, 2H), 7.97-7.93 (m, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.80 (d, J =7.8 Hz, 1H), 7.40 (s, 1H), 2.55 (s, 3H). DMSO  381.0, 383.0 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 182

390.82 1H-NMR (400 MHz, DMSO-d6): δ 12.25 (s, 1H), 9.54 (s, 1H), 9.25(s, 1H), 8.84-8.80 (m, 2H), 8.09 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.88(d, J = 8.0 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.77-7.75 (m, 1H), 7.29(d, J = 8.4 Hz, 1H), 2.56 (s, 3H). DMSO  391.1, 393.0 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 183

366.34 1H-NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1H), 9.50 (d, J = 1.6 Hz,1H), 8.69 (dd, J = 4.8, 1.6 Hz, 1H), 8.66-8.63 (m, 1H), 8.30 (s, 1H),7.99-7.95 (m, 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.76 (dd, J = 8.6, 1.4 Hz,1H), 7.58-7.55 (m, 1H), 2.55 (s, 3H). DMSO 367.1 (M + 1), 184.1(M/2 + 1) Method A (TFA) 95 Meth-od C, G1 184

415.7 1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 9.51 (s, 1H),8.75-8.72 (m, 2H), 8.38 (s, 2H), 8.32 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H),7.77 (d, J = 8.0 Hz, 1H), 7.66-7.64 (m, 1H), 2.55 (s, 3H). DMSO  414.8,416.8 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 185

354.4 1H-NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.56 (s, 1H), 8.93 (d,J = 8.0 Hz, 1H), 8.81 (d, J = 4.0 Hz, 1H), 8.65 (s, 1H), 8.48 (s, 1H),8.21 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.88-7.88 (m, 3H),7.65 (t, J = 7.6 Hz, 1H), 2.65 (s, 3H), 2.58 (s, 3H). DMSO 355.1 (M +1), 178.1 (M/2 + 1) Method A (TFA) 95 Meth-od C, G1 186

356.38 1H-NMR (400 MHz, DMSO-d6): δ 12.18 (s, 1H), 9.57 (s, 1H), 9.07(d, J = 8.4 Hz, 1H), 8.71 (d, J = 5.6 Hz, 2H), 8.10 (d, J = 8.0 Hz, 1H),7.99 (s, 1H), 7.86-7.76 (m, 3H), 7.58 (t, J = 6.2 Hz, 1H), 7.23 (t, J =7.4 Hz, 1H), 2.55 (s, 3H). DMSO 357.1 (M + 1) Method A (TFA) 95 Meth-odC, G1 187

337.38 1H-NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 9.51 (s, 1H),8.65-8.70 (m, 2H), 3.45 (s, 1H), 8.38 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H),7.83 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.8 Hz,1H), 7.62 (d, J = 7.2 Hz, 1H), 7.54-7.57 (m, 1H), 2.56 (s, 3H). DMSO338.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 188

355.39 1H-NMR (400 MHz, DMSO-d6): δ 13.11 (s, 1H), 9.61 (s, 1H), 9.09(d, J = 8.8 Hz, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.81 (s, 1H), 8.50 (s,1H), 8.01-7.98 (m, 2H), 7.96 (dd, J = 7.8, 1.0 Hz, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.78-7.72 (m, 3H), 7.23 (t, J = 7.4 Hz, 1H), 2.56 (s, 3H). DMSO356.2 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 189

385.42 1H-NMR (400 MHz, DMSO-d6): δ 12.62 (s, 1H), 9.58 (s, 1H), 9.03(d, J = 8.4 Hz, 1H), 8.92 (d, J = 4.0 Hz, 1H), 8.74-8.69 (m, 2H),7.92-7.87 (m, 2H), 7.72 (t, J = 7.6 Hz, 1H), 7.66-7.56 (m, 3H), 7.23 (t,J = 7.6 Hz, 1H), 4.00 (s, 3H), 2.84 (d, J = 4.4 Hz, 3H). DMSO 386.2(M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 190

461.51 1H-NMR (400 MHz, DMSO-d6): δ 12.40 (s, 1H), 9.57 (d, J = 1.2 Hz,1H), 9.48 (t, J = 6.0 Hz, 1H), 8.89 (d, J = 8.8 Hz, 1H), 8.73-8.68 (m,2H), 7.96 (dd, J = 8.0, 1.2 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.76-7.72(m, 1H), 7.61-7.55 (m, 3H), 7.34-7.20 (m, 6H), 4.52 (d, J = 5.6 Hz, 2H),3.93 (s, 3H). DMSO 462.2 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 191

368.77 1H NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.55-9.45 (m, 1H),8.93-8.76 (m, 2H), 8.63 (d, J = 8.9 Hz, 1H), 8.10 (ddd, J = 13.2, 7.5,2.6 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.80-7.67 (m, 3H), 7.62-7.49 (m,1H). DMSO  369.0, 371.0 (M + 1) Method B (NH4HCO3) 97 Meth-od C, G1 192

401.68 1H NMR (300 MHz, DMSO-d6): δ 10.38 (s, 1H), 9.58-9.43 (m, 1H),8.90-8.79 (m, 2H), 8.65 (d, J = 9.0 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H),8.01-7.90 (m, 2H), 7.82-7.68 (m, 3H). DMSO  401.0,  403.0, 405.0 (M + 1)Method B (NH4HCO3) 97 Meth-od C, G1 193

367.23 1H NMR (300 MHz, DMSO-d6): δ 10.19 (s, 1H), 9.53 (d, J = 2.1 Hz,1H), 8.78-8.56 (m, 3H), 8.17 (t, J = 2.0 Hz, 1H), 7.96 (d, J = 2.1 Hz,1H), 7.93-7.85 (m, 1H), 7.75 (dd, J = 8.9, 2.2 Hz, 1H), 7.58 (ddd, J =8.0, 4.8, 0.7 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.26 (ddd, J = 8.0,2.0, 0.8 Hz, 1H). DMSO  367.0, 369.0 (M + 1) Method B (NH4HCO3) 98Meth-od C, G1 194

376.80 1H NMR (300 MHz, DMSO-d6): δ 13.11 (s, 1H), 10.27 (s, 1H), 9.58(d, J = 2.1 Hz, 1H), 8.87-8.62 (m, 4H), 8.21-8.10 (m, 1H), 7.96 (d, J =2.1 Hz, 1H), 7.82-7.68 (m, 2H), 7.64-7.53 (m, 2H). DMSO  377.0, 379.0(M + 1) Method A (TFA) 95 Meth-od C, G1 195

401.68 1H NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.52-9.49 (m, 1H),8.85-8.73 (m, 2H), 8.61 (d, J = 9.0 Hz, 1H), 8.18-8.08 (m, 2H),7.99-7.95 (m, 1H), 7.77 (dd, J = 8.9, 2.2 Hz, 1H), 7.71 (dd, J = 7.8,5.0 Hz, 1H), 7.42-7.39 (m, 1H). DMSO  401.0,  403.0, 405.0 (M + 1)Method B (NH4HCO3) 97 Meth-od C, G1 196

386.76 1H-NMR (300 MHz, DMSO-d6): δ 10.43 (s, 1H), 9.49 (d, J = 1.9 Hz,1H), 8.95-8.82 (m, 2H), 8.64 (d, J = 9.0 Hz, 1H), 8.01-7.82 (m, 4H),7.78 (dd, J = 8.9, 2.2 Hz, 1H). DMSO  387.0, 389.1 (M + 1) Method B(NH4HCO3) 97 Meth-od C, G1 197

411.86 1H NMR (400 MHz, DMSO-d6): δ 10.50 (brs, 1H), 9.56 (s, 1H),9.08-8.93 (m, 1H), 8.92-8.82 (m, 1H), 8.73 (d, J = 8.9 Hz, 1H),8.21-8.11 (m, 2H), 8.02 (d, J = 1.9 Hz, 1H), 7.98-7.77 (m, 4H), 7.38 (s,2H). DMSO  412.1, 414.1 (M + 1) Method B (NH4HCO3) 97 Meth-od C, G1 198

385.22 1H NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 9.51 (d, J = 1.4 Hz,1H), 8.77-8.69 (m, 2H), 8.60 (d, J = 9.0 Hz, 1H), 8.27-8.20 (m, 1H),7.97 (d, J = 2.1 Hz, 1H), 7.90 (ddd, J = 9.0, 4.3, 2.6 Hz, 1H), 7.76(dd, J = 8.9, 2.1 Hz, 1H), 7.64 (dd, J = 8.0, 4.9 Hz, 1H), 7.55 (t, J =9.1 Hz, 1H). DMSO  385.0, 387.0 (M + 1) Method B (NH4HCO3) 100  Meth-odC, G1 199

357.80 1H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 9.53-9.49 (m, 1H),8.81-8.70 (m, 2H), 8.64 (d, J = 8.9 Hz, 1H), 8.45-8.36 (m, 1H),8.29-8.21 (m, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.9, 2.1 Hz,1H), 7.74-7.61 (m, 3H). DMSO  357.9, 359.9 (M + 1) Method B (NH4HCO3) 99Meth-od C, G1 200

435.23 1H-NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 9.53 (s, 1H),8.84-8.74 (m, 2H), 8.69-8.61 (m, 2H), 8.26 (dd, J = 8.8, 2.6 Hz, 1H),7.99 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 8.9,2.1 Hz, 1H), 7.70 (dd, J = 7.7, 5.3 Hz, 1H). DMSO  435.0, 437.0 (M + 1)Method B (NH4HCO3) 99 Meth-od C, G1 201

400.78 1H-NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1H), 9.53 (d, J = 1.5 Hz,1H), 3.85 (d, J = 8.1 Hz, 1H), 8.82 (dd, J = 5.0, 1.4 Hz, 1H), 8.69 (d,J = 9.0 Hz, 1H), 8.49 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.99 (d, J =2.1 Hz, 1H), 7.83-7.67 (m, 3H), 7.56 (d, J = 7.8 Hz, 1H). DMSO  401.1,403.0 (M + 1) Method B (NH4HCO3) 99 Meth-od C, G1 202

375.79 1H-NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.49 (s, 1H),8.87-8.77 (m, 2H), 8.63 (d, J = 8.9 Hz, 1H), 8.42 (dd, J = 5.8, 2.7 Hz,1H), 8.26 (ddd, J = 9.1, 4.9, 2.8 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H),7.83-7.72 (m, 2H), 7.66 (t, J = 9.1 Hz, 1H). DMSO  375.9, 377.9 (M + 1)Method B (NH4HCO3) 99 Meth-od C, G1 203

348.35 1H-NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.51 (s, 1H), 8.91(d, J = 6.8 Hz, 1H), 8.86 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 8.3 Hz, 1H),8.11 (ddd, J = 13.0, 7.5, 2.5 Hz, 1H), 7.90-7.68 (m, 3H), 7.65-7.46 (m,2H), 2.56 (s, 3H). DMSO 349.1 (M + 1) Method B (NH4HCO3) 100  Meth-od C,G1 204

381.26 1H-NMR (400 MHz, DMSO-d6): δ 10.05 (s, 1H), 9.54 (s, 1H),8.75-8.65 (m, 2H), 8.46 (d, J = 8.5 Hz, 1H), 8.42 (d, J = 2.4 Hz, 1H),7.98 (dd, J = 8.8, 2.4 Hz, 1H), 7.72 (d, J = 9.1 Hz, 2H), 7.57 (dd, J =7.9, 4.9 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 2.55 (s, 3H). DMSO  381.0,383.0 (M + 1) Method B (NH4HCO3) 100  Meth-od C, G1 205

364.35 1H-NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1H), 9.53 (s, 1H),8.79-8.58 (m, 2H), 8.49 (d, J = 9.0 Hz, 1H), 8.13 (ddd, J = 9.2, 7.1,1.7 Hz, 1H), 7.84-7.65 (m, 1H), 7.67-7.46 (m, 2H), 7.41-7.23 (m, 2H),3.97 (s, 3H). DMSO 365.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 206

364.80 1H-NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.50 (d, J = 1.4 Hz,1H), 8.92-8.77 (m, 2H), 8.53 (d, J = 8.5 Hz, 1H), 8.24 (dd, J = 6.8, 2.5Hz, 1H), 7.98-7.87 (m, 1H), 7.83-7.70 (m, 2H), 7.60-7.50 (m, 2H), 2.56(s, 3H). DMSO  365.1, 367.1 (M + 1) Method B (NH4HCO3) 100  Meth-od C,G1 207

381.26 1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.53 (s, 1H),8.87-8.73 (m, 2H), 8.50 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 1.7 Hz, 2H),7.77 (s, 1H), 7.72 (dd, J = 7.8, 5.1 Hz, 1H), 7.57 (dd, J = 8.4, 0.9 Hz,1H), 7.39 (t, J = 1.6 Hz, 1H), 2.56 (s, 3H). DMSO  381.1, 383.0 (M + 1)Method B (NH4HCO3) 99 Meth-od C, G1 208

337.38 1H-NMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 9.53 (d, J = 1.6 Hz,1H), 8.77-8.63 (m, 2H), 8.53-8.42 (m, 2H), 8.28 (d, J = 8.3 Hz, 1H),7.75 (s, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H),7.60-7.51 (m, 2H), 2.55 (s, 3H). DMSO 338.2 (M + 1) Method B (NH4HCO3)100  Meth-od C, G1 209

355.39 1H-NMR (400 MHz, DMSO-d6): δ 13.09 (s, 1H), 9.60 (s, 1H), 9.02(d, J = 8.4 Hz, 1H), 8.96 (d, J = 8.4 Hz, 1H), 8.85 (d, J = 4.0 Hz, 1H),8.49 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.92(s, 1H), 7.83 (dd, J = 8.0, 5.2 Hz, 1H), 7.80 (s, 1H), 7.73 (t, J = 7.4Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 2.56 (s,3H). DMSO 356.1 (M + 1) Method B (NH4HCO3) 99 Meth-od C, G1 210

375.81 1H-NMR (400 MHz, DMSO-d6): 13.13 (s, 1H), 9.59 (s, 1H), 9.03-8.89(m, 3H), 3.50 (s, 1H), 8.21-8.19 (d, J = 8.6 Hz, 1H), 7.99-7.87 (m, 4H),7.82-7.79 (dd, J = 8.8, 2.3 Hz, 1H), 7.74-7.70 (m, 1H), 7.28-7.24 (m,1H). DMSO  376.1, 378.1 (M + 1) Method B (NH4HCO3) 98 Meth-od C, G1 211

444.79 1H-NMR (400 MHz, DMSO-d6): δ 13.68 (brs, 1H), 11.98 (s, 1H), 9.49(s, 1H), 8.83-8.64 (m, 2H), 8.11-7.90 (m, 3H), 7.81 (d, J = 2.0 Hz, 1H),7.75-7.62 (m, 2H), 7.22 (t, J = 7.6 Hz, 1H). DMSO  444.9, 446.9 (M + 1)Method B (NH4HCO3) 100  Meth-od C, G1 212

HCl 466.79 1H-NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 9.62 (s, 1H),8.90 (dd, J = 8.2, 1.3 Hz, 1H), 8.69 (d, J = 9.0 Hz, 1H), 8.05 (d, J =8.2 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.92-7.86 (m, 1H), 7.86-7.79 (m,1H), 7.77 (dd, J = 8.9, 2.1 Hz, 1H), 7.53 (t, J = 8.2 Hz, 1H), 7.30 (t,J = 73.3 Hz, 1H), 7.04 (dd, J = 8.1, 2.1 Hz, 1H). DMSO  466.9, 468.9(M + 1) Method B (NH4HCO3) 100  Meth-od C, G1 213

469.67 1H-NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 9.57 (s, 1H), 8.85(dd, J = 8.1, 1.3 Hz, 1H), 8.60 (d,. J = 9.0 Hz, 1H), 8.35-8.23 (m, 1H),8.06 (d, J = 8.2 Hz, 1H), 8.00-7.90 (m, 2H), 7.80-7.65 (m, 2H). DMSO 468.9, 470.8 (M + 1) Method B (NH4HCO3) 100  Meth-od C, G1 214

436.77 1H-NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 9.56 (s, 1H), 8.84(d, J = 8.3 Hz, 1H), 8.64 (d, J = 9.0 Hz, 1H), 8.14-7.99 (m, 2H), 7.95(d, J = 2.1 Hz, 1H), 7.81-7.65 (m, 2H), 7.59-7.48 (m, 1H). DMSO  436.9,438.9 (M + 1) Method B (NH4HCO3) 100  Meth-od C, G1 215

440.37 1H-NMR (400 MHz, DMSO-d6): δ 13.81 (brs, 1H), 11.97 (s, 1H), 9.57(s, 1H), 9.01-8.91 (m, 1H), 8.84 (d, J = 8.3 Hz, 1H), 8.06 (dd, J = 7.9,1.4 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H),7.79-7.70 (m, 1H), 7.52 (dd, J = 9.1, 2.6 Hz, 1H), 7.49-7.44 (m, 1H),7.20 (t, J = 7.6 Hz, 1H), 3.94 (s, 3H). DMSO 441.1 (M + 1) Method B(NH4HCO3) 100  Meth-od C, G1 216

396.80 1H-NMR (400 MHz, DMSO-d6): δ 11.89 (s, 1H), 9.80 (s, 1H), 8.34(dd, J = 9.6, 2.6 Hz, 1H), 8.22 (s, 1H), 8.11 (dd, J = 6.9, 2.6 Hz, 1H),7.88 (d, J = 2.7 Hz, 1H), 7.84-7.77 (m, 1H), 7.74 (d, J = 9.1 Hz, 1H),7.56-7.43 (m, 2H), 6.44 (d, J = 9.6 Hz, 1H), 3.95 (s, 3H). DMSO  397.1,399.1 (M + 1) Method B (NH4HCO3) 100  Meth-od C, G1 217

410.37 1H-NMR (400 MHz, DMSO-d6): δ 11.89 (s, 1H), 9.80 (s, 1H), 8.36(dd, J = 9.6, 2.6 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.92 (d, J = 2.6Hz, 1H), 7.80-7.67 (m, 3H), 7.53-7.46 (m, 2H), 7.27 (t, J = 74.0 Hz,1H), 6.98 (dd, J = 8.2, 2.0 Hz, 1H), 6.43 (d, J = 9.5 Hz, 1H), 3.96 (s,3H). DMSO 411.1 (M + 1) Method B (NH4HCO3) 100  Meth-od C, G1 218

387.39 1H-NMR (400 MHz, DMSO-d6): δ 12.98 (s, 1H), 12.58-12.05 (m, 1H),8.55 (s, 2H), 8.41 (s, 1H), 8.33 (dd, J = 9.7, 2.5 Hz, 1H), 8.11-7.98(m, 1H), 7.97- 7.86 (m, 2H), 7.79-7.64 (m, 3H), 7.44-7.29 (m, 1H), 6.52(d, J = 9.7 Hz, 1H), 3.98 (s, 3H). DMSO 388.2 (M + 1) Method B (NH4HCO3)100  Meth-od C, G1 219

389.38 1H-NMR (400 MHz, DMSO-d6): δ 12.73 (s, 1H), 9.56 (s, 1H), 9.10(dd, J = 8.9, 5.4 Hz, 1H), 8.79-8.63 (m, 2H), 8.50 (s, 1H), 8.08 (s,1H), 7.95-7.76 (m, 2H), 7.68-7.45 (m, 4H), 3.97 (s, 3H). DMSO 390.1(M + 1) Method B (NH4HCO3) 98 Meth-od C, G1 220

369.80 1H-NMR (400 MHz, DMSO-d6): δ 14.87 (brs, 1H), 10.08 (brs, 1H),8.85-7.66 (m, 6H), 7.69-6.63 (m, 3H), 3.96 (s, 3H). DMSO  397.1, 399.1(M + 1) Method B (NH4HCO3) 100  Meth-od C, G1 221

387.39 1H-NMR (400 MHz, DMSO-d6): δ 14.80 (brs, 1H), 13.19 (s, 1H), 8.68(d, J = 7.3 Hz, 1H), 8.44 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.13 (d, J= 9.1 Hz, 1H), 8.10-8.03 (m, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.90 (s,1H), 7.86 (s, 1H), 7.78-7.65 (m, 2H), 7.43 (t, J = 7.5 Hz, 1H), 6.78 (t,J = 6.8 Hz, 1H), 3.99 (s, 3H). DMSO 388.1 (M + 1) Method B (NH4HCO3)100  Meth-od C, G1 222

410.37 1H-NMR (400 MHz, DMSO-d6): δ 15.33 (brs, 1H), 13.47 (brs, 1H),11.69 (s, 1H), 8.62 (dd, J = 7.5, 2.1 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H),8.17 (d, J = 9.2 Hz, 1H), 8.07 (dd, J = 6.2, 2.1 Hz, 1H), 7.81-7.68 (m,3H), 7.61 (t, J = 8.1 Hz, 1H), 7.32 (t, J = 74.0 Hz, 1H), 7.26-7.18 (m,1H), 6.80-6.69 (m, 1H), 4.03 (s, 3H). DMSO 411.1 (M + 1) Method B(NH4HCO3) 100  Meth-od C, G1 223

401.22 1H-NMR (400 MHz, DMSO-d6): δ 11.22 (brs, 1H), 8.47 (d, J = 8.8Hz, 1H), 8.30 (dd, J = 9.6, 2.3 Hz, 1H), 8.27- 8.18 (m, 1H). 8.11 (dd, J=- 6.8, 2.4 Hz, 1H), 7.90-7.73 (m, 2H), 7.60 (dd, J = 8.8, 1.8 Hz, 1H),7.47 (t, J = 9.1 Hz, 1H), 6.44 (d, J = 9.6 Hz, 1H). DMSO  401.0, 403.0(M + 1) Method B (NH4HCO3) 100  Meth-od C, G1 224

414.79 1H-NMR (400 MHz, DMSO-d6): δ 12.00 (s, 1H), 10.07 (s, 1H), 8.54(d, J = 8.9 Hz, 1H), 8.34 (dd, J = 9.6, 2.6 Hz, 1H), 8.30 (d, J = 2.3Hz, 1H), 7.87-7.69 (m, 3H), 7.62 (dd, J = 8.9, 2.1 Hz, 1H), 7.48 (t, J =8.2 Hz, 1H), 7.26 (t, J = 74.0 Hz, 1H), 7.00 (dd, J = 8.1, 2.0 Hz, 1H),6.44 (d, J = 9.6 Hz, 1H). DMSO  415.1, 417.1 (M + 1) Method B (NH4HCO3)100  Meth-od C, G1 225

432.78 1H-NMR (400 MHz, DMSO-d6): δ 12.06 (s, 1H), 10.15 (s, 1H), 8.55(d, J = 9.0 Hz, 1H), 8.34 (dd, J = 9.6, 2.5 Hz, 1H), 8.29 (s, 1H), 7.97(s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.65 (dd, J= 8.8, 2.1 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H),6.44 (d, J = 9.6 Hz, 1H). DMSO  433.0, 435.0 (M + 1) Method B (NH4HCO3)100  Meth-od C, G1 226

428.36 1H-NMR (400 MHz, DMSO-d6): δ 12.28 (brs, 1H), 8.47-8.06 (m, 3H),8.06-7.76 (m, 3H), 7.67-7.59 (m, 2H), 7.28 (s, 1H), 6.47 (d, J = 9.7 Hz,1H), 3.98 (s, 3H). DMSO 429.1 (M + 1) Method B (NH4HCO3) 94 Meth-od C,G1 227

401.42 1H-NMR (400 MHz, DMSO-d6): δ 12.97 (s, 1H), 12.27 (s, 1H),8.73-8.56 (m, 1H), 8.53 (s, 1H), 8.42 (s, 1H), 8.33 (dd, J = 9.7, 2.6Hz, 1H), 8.04-7.86 (m, 3H), 7.74-7.59 (m, 3H), 7.34 (t, J = 8.7 Hz, 1H),6.52 (d, J = 9.7 Hz, 1H), 4.23 (q, J = 6.9 Hz, 2H), 1.45 (t, J = 6.9 Hz,3H). DMSO 402.2 (M + 1) Method B (NH4HCO3) 100  Meth-od C, G1 228

465.91 1H-NMR (400 MHz, DMSO-d6): δ 8.43-8.31 (m, 2H), 8.27 (s, 1H),8.14 (dd, J = 6.7, 2.3 Hz, 1H), 7.89-7.70 (m, 3H), 7.47 (t, J = 9.1 Hz,1H), 6.44 (d, J = 9.6 Hz, 1H), 3.62 (d, J = 9.3 Hz, 6H), 2.42 (s, 4H).DMSO  466.1, 468.1 (M + 1) Method B (NH4HCO3) 97 Meth-od C, G1 229

436.41 1H-NMR (400 MHz, DMSO-d6): δ 10.28 (brs, 1H), 9.47 (s, 1H), 8.91(d, J = 7.2 Hz, 1H), 8.84 (d, J = 5.2 Hz, 1H), 8.08-8.06 (m, 2H), 7.91(d, J = 7.6 Hz, 1H), 7.85 (t, J = 8 Hz, 1H), 7.65-7.60 (m, 2H),7.54-7.52 (m, 1H), 4.17 (t, J = 7.6 Hz, 2H), 1.86 (q, J = 6.8 Hz, 2H),1.08-1.03 (m, 3H). DMSO 423.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C,G1 230

403.41 1H-NMR (400 MHz, DMSO-d6): δ 13.42 (s, 1H), 9.53 (s, 1H), 9.10(d, J = 12.8 Hz, 1H), 8.70-8.65 (m, 2H), 8.50 (s, 1H), 8.07-8.04 (m,2H), 7.86 (d, J = 8.8 Hz, 1H), 7.60-7.55 (m, 2H), 7.48 (s, 1H),7.06-7.01 (m, 1H), 4.21 (q, J = 6.8 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H).DMSO 403.9 (M + 1) Method A (TFA) 95 Meth-od C, G1 231

440.42 1H-NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1H), 9.48 (s, 1H), 9.01(d, J = 7.6 Hz, 1H), 8.90 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 8.04 (s,1H), 7.98 (d, J = 8.8 Hz, 2H), 7.93 (t, J = 5.8 Hz, 1H), 7.64-7.60 (m,2H), 7.22 (d, J = 8.4 Hz, 1H), 4.19 (t, J = 6.4 Hz, 1H), 1.87-1.81 (m,2H), 1.06 (t, J = 7.2 Hz, 3H). DMSO 440.9 (M + 1) Method A (TFA) 95Meth-od C, G1 232

359.12 1H-NMR (400 MHz, DMSO-d6): δ 13.10 (s, 1H), 9.54 (s, 1H), 8.96(d, J = 8.4 Hz, 8.22-8.17 (m, 1H), 7.97-7.93 (m, 2H), 7.70-7.59 (m, 4H),7.21 (t, J = 8.0 Hz, 1H). DMSO 360.1 (M + 1) Method B (NH4HCO3) 95Meth-od C, G1 233

381.26 1H-NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 9.08 (s, 1H),8.67-8.70 (m, 1H), 3.64 (d, J = 8.0 Hz, 1H), 7.98 (s, 2H), 7.76-7.73 (m,2H), 7.55-7.57 (m, 1H), 7.43-7.46 (m, 1H), 7.36 (s, 1H), 2.99 (s, 3H).DMSO  381.0,  383.0, 385.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1234

HCl 408.4 1H-NMR (400 MHz, DMSO-d6): δ 10.38 (s, 1H), 9.51 (s, 1H), 9.00(d, J = 7.2 Hz, 1H), 8.88 (d, J = 4.8 Hz, 1H), 8.13 (s, 1H), 7.96 (d, J= 7.2 Hz, 1H), 7.88-7.91 (m, 2H), 7.86 (s, 1H), 7.80 (d, J = 8.4 Hz,1H), 7.63 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 9.2, 2.0 Hz,. 1H), 7.55 (t,J = 8.4 Hz, 1H), 7.31 (t, J = 74.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H),4.28 (q, J = 6.8 Hz, 2H), 1.46 (t, J = 6.8 Hz, 3H). DMSO 409.2 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 235

412.36 1H-NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 9.49 (s, 1H), 9.02(d, J = 8.4 Hz, 1H), 8.91 (dd, J = 5.2, 1.2 Hz, 1H), 8.31 (d, J = 2.0Hz, 1H), 8.06 (s, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.94-7.91 (m, 1H),7.64-7.60 (m, 2H), 7.22 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H). DMSO 412.9(M + 1) Method A (TFA) 95 Meth-od C, G1 236

395.46 1H-NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.90 (s, 1H), 8.77(dd, J = 13.5, 6.2 Hz, 2H), 8.19 (d, J = 9.2 Hz, 1H), 7.81 (dd, J = 9.2,2.4 Hz, 1H), 7.72=7.56 (m, 3H), 7.33 (d, J = 2.0 Hz, 1H), 4.15 (q, J =6.8 Hz, 2H), 2.39 (s, 3H), 2.35 (s, 3H), 1.38 (t, J = 6.8 Hz, 3H). DMSO396.2 (M + 1) Method B (NH4HCO3) 98 Meth-od C, G1 237

376.8 1H-NMR (400 MHz, DMSO-d6): δ 11.64 (brs, 1H), 11.31 (brs, 1H),9.45 (s, 1H), 8.82-8.69 (m, 1H), 8.61 (s, 1H), 8.15 (d, J = 2.0 Hz, 1H),8.04-7.91 (m, 1H), 7.81 (dd, J = 8.9, 2.1 Hz, 1H), 7.70-7.55 (m, 1H),7.47 (s, 1H), 7.06 (s, 1H), 5.98 (d, J = 8.2 Hz, 1H). DMSO  376.9, 378.9(M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 238

412.23 1H-NMR (400 MHz, DMSO-d6): δ 10.70 (s, 1H), 9.62 (d, J = 2.4 Hz,1H), 9.51 (d, J = 1.6 Hz, 1H), 8.76-8.79 (m, 2H), 8.57 (dd, J = 6.8, 2.0Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.94 (dd, J= 6.8, 2.0 Hz, 1H), 7.71 (m, 2H). DMSO  412.0,  414.0, 416.0 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 239

381.26 1H-NMR (400 MHz, DMSO-d6): 10.04 (s, 1H), 9.59 (d, J = 1.2 Hz,1H), 8.74-8.70 (m, 2H), 8.42-8.39 (m, 2H), 7.98 (dd, J = 2.4 Hz, 1H),7.79 (d, J = 7.2 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.59-7.55 (m, 2H),2.75 (s, 3H). DMSO  381,    383    (M + 1) Method B (NH4HCO3) 95 Meth-odC, G1 240

348.35 1H-NMR (400 MHz, DMSO-d6): 10.00 (s, 1H), 9.57 (d, J = 1.2 Hz,1H), 8.72-8.70 (m, 2H), 8.38 (d, J = 8.4 Hz, 1H), 8.17-8.12 (m, 1H),7.79-7.74 (m, 2H), 7.59-7.50 (m, 3H), 2.74 (s, 3H). DMSO 349.2 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 241

355.39 1H-NMR (400 MHz, DMSO-d6): 11.10 (s, 1H), 9.60 (d, J = 1.6 Hz,1H), 9.16 (d, J = 8.4 Hz, 1H), 8.82-8.72 (m, 2H), 8.50 (s, 1H), 8.04 (d,J = 8.4 Hz, 1H), 7.97-7.92 (m, 2H), 7.77-7.72 (m, 2H), 7.63-7.60 (m,2H), 7.24-7.19 (m, 1H), 2.76 (s, 3H). DMSO 356.2 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 242

337.4 1H-NMR (400 MHz, DMSO-d6): 10.12 (s, 1H), 9.57 (s, 1H), 8.73-8.70(m, 2H), 8.46 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 8.0 Hz,1H), 7.80 (d, J = 7.6 Hz, 1H), 7.72-7.56 (m, 4H), 2.76 (s, 3H). DMSO338.2 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 243

396.37 1H-NMR (400 MHz, DMSO-d6): 10.07 (s, 1H), 9.59 (s, 1H), 8.75-8.69(m, 2H), 8.44 (d, J = 8.0 Hz, 1H), 8.20 (s, 1H), 7.97-7.94 (m, 1H), 7.89(d, J = 7.2 Hz, 1H), 7.62-7.54 (m, 3H), 7.16 (d, J = 8.4 Hz, 1H), 2.76(s, 3H). DMSO 397.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 244

378.37 1H-NMR (400 MHz, DMSO-d6): 9.98 (s, 1H), 9.60 (s, 1H), 8.75-8.69(m, 2H), 8.44 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.84 (d, J = 7.6 Hz,1H), 7.79 (d, J = 6.8 Hz, 1H), 7.58-7.00 (m, 4H), 6.98 (d, J = 2.0 Hz,1H), 2.76 (s, 3H). DMSO 379.2 (M + 1) Method B (NH4HCO3) 95 Meth-od C,G1 245

360.34 1H-NMR (400 MHz, DMSO-d6): δ 11.95-11.11 (m, 2H), 9.43 (d, J =1.6 Hz, 1H), 8.71 (dd, J = 4.7, 1.5 Hz, 1H), 8.56 (td, J = 8.0, 1.9 Hz,1H), 8.15 (dd, J = 9.2, 5.3 Hz, 1H), 8.08 (dd, J = 9.4, 2.7 Hz, 1H),8.02-7.88 (m, 2H), 7.54 (dd, J = 7.90, 4.81 Hz, 1H), 7.50-7.40 (m, 1H),7.04 (t, J = 7.1 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H). DMSO 360.8 (M + 1)Method B (NH4HCO3) 95 Meth-od C, G1 246

393.8 1H-NMR (400 MHz, DMSO-d6): δ 13.29 (s, 1H), 9.54 (s, 1H), 9.29 (s,1H), 8.06 (d, J = 0.9 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.82 (dd, J =26.4, 8.4 Hz, 2H), 7.58 (dd, J = 7.9, 4.8 Hz, 1H), 7.28 (d, J = 8.0 Hz,1H), 8.72 (d, J = 3.6 Hz, 1H), 8.67 (d, J = 7.8 Hz, 1H), 8.64-8.53 (m,1H). DMSO  394.0, 396.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 247

1H-NMR (400 MHz, DMSO-d6): δ 13.36 (brs, 1H), 9.54 (s, 1H), 9.36-9.08(m, 1H), 8.12 (d, J = 8.8 Hz, 2H), 8.08-7.96 (m, 1H), 7.94-7.78 (m, 2H),7.57 (dd, J = 7.8, 4.8 Hz, 1H), 7.29- 7.16 (m, 1H), 8.94-8.49 (m, 3H).DMSO 444.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 248

376.8 1H-NMR (400 MHz, DMSO-d6): δ 9.57 (s, 1H), 8.71 (d, J = 5.6 Hz,2H), 8.40 (d, J = 1.8 Hz, 1H), 8.01-7.97 (m, 2H), 7.89 (dd, J = 7.8, 1.5Hz, 1H), 7.63-7.51 (m, 1H), 7.29 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 8.4Hz, 1H), 6.76-6.74 (m, 1H). DMSO  377.0, 379.0 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 249

426.35 1H-NMR (400 MHz, DMSO-d6): δ 9.70 (d, J = 1.5 Hz, 1H), 8,74 (td,J = 8.0, 1.9 Hz, 1H), 8.71 (dd, J = 4.7, 1.7 Hz, 1H), 8.50 (d, J = 9.0Hz, 1H), 7.88 (dd, J = 7.8, 1.9 Hz, 1H), 7.76 (d, J = 1.1 Hz, 1H),7.20-7.11 (m, 1H), 7.64-7.56 (m, 2H)., 6.70-6.60 (m, 1H), 6.52 (dd, J =10.8, 3.9 Hz, 1H). DMSO 427.1 (M + 1) Method B (NH4HCO3) 95 Meth-od C,G1 250

360.34 1H-NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.83 (d, J = 7.4 Hz,1H), 8.71 (d, J = 3.9 Hz, 1H), 8.49 (t, J = 7.2 Hz, 1H), 7.85 (d, J =7.8 Hz, 1H), 7.63-7.51 (m, 3H), 7.14 (t, J = 7.0 Hz, 1H), 6.61 (d, J =8.0 Hz, 1H), 6.46 (t, J = 7.2 Hz, 1H). DMSO 360.8 (M + 1) Method B(NH4HCO3) 95 Meth-od C, G1 251

400.43 1H-NMR (400 MHz, DMSO-d6): δ 12.92 (s, 1H), 9.04 (d, J = 8.3 Hz,1H), 8.66 (dd, J = 7.7, 1.7 Hz, 1H), 8.48 (s, 1H), 8.10 (dd, J = 4.6,1.7 Hz, 1H), 8.01-7.94 (m, 2H), 7.89 (d, J = 8.9 Hz, 1H), 7.72 (t, J =7.7 Hz, 1H), 7.55 (m, 2H), 7.20 (t, J = 7.5 Hz, 1H), 6.74 (dd, J = 7.7,4.7 Hz, 1H), 4.24 (q, J = 6.9 Hz, 2H), 1.46 (t, J = 6.9 Hz, 3H). DMSO401.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 252

483.44 1H-NMR (400 MHz, DMSO-d6): δ 13.28 (s, 1H), 9.54 (s, 1H), 9.28(s, 1H), 8.70-8.66 (m, 2H), 8.59 (s, 1H), 8.11 (d, J = 8.8 Hz, 2H), 7.90(d, J = 8.9 Hz, 1H), 7.64-7.49 (m, 3H), 7.18 (d, J = 8.2 Hz, 1H), 4.14(t, J = 6.2 Hz, 2H), 1.86 (q, J = 6.8 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H).DMSO 484.0 (M + 1) Method B (NH4HCO3) 95 Meth-od C, G1 253

1H-NMR (400 MHz, DMSO-d6): δ 13.24 (s, 1H), 9.56 (s, 1H), 9.39 (d, J =2.1 Hz, 1H), 8.77-8.73 (m, 2H), 8.55 (s, 1H), 8.09 (s, 1H), 8.00 (d, J =8.6 Hz, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.65 (dd, J = 7.9, 4.9 Hz, 1H),7.59 (dd, J = 9.1, 2.5 Hz, 1H), 4.24 (q, J = 6.9 Hz, 2H), 1.46 (t, J =6.9 Hz, 3H). DMSO  420.0, 422.0 (M + 1) Method B (NH4HCO3) 95 Meth- odC, G1 254

469.42 1H-NMR (400 MHz, DMSO-d6): δ 13.34 (s, 1H), 9.60 (s, 1H), 9.35(s, 1H), 8.77 (d, J = 3.5 Hz, 1H), 8.72 (d, J = 7.9 Hz, 1H), 8.67 (s,1H), 8.22 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H),7.69-7.58 (m, 2H), 7.55 (s, 1H), 7.24 (d, J = 8.5 Hz, 1H), 4.29 (q, J =7.0 Hz, 2H), 1.53 (t, J = 6.9 Hz, 3H). DMSO 470.2 (M + 1) Method B(NH4HCO3) 95 Meth- od C, G1 255

403.41 1H-NMR (400 MHz, DMSO-d6): δ 11.43 (s, 1H), 9.53 (s, 1H),8.68-8.66 (m, 2H), 8.56 (d, J = 8.3 Hz, 1H), 8.23 (s, 1H), 8.12 (s, 1H),7.88 (d, J = 9.1 Hz, 1H), 7.72-7.64 (m, 1H), 7.61-7.47 (m, 3H),7.17-7.08 (m, 1H), 4.23 (q, J = 6.9 Hz, 2H), 1.46 (t, J = 6.9 Hz, 3H).DMSO 404.2 (M + 1) Method B (NH4HCO3) 95 Meth- od C, G1 Reten- Puri-Meth- Molecu- tion LCMS ty od of Salt lar ¹H NMR Time Pro- per- Coup-Number Product Type Mass ¹H NMR Solvent LCMS (min) tocol cent ling 256

HCl 456.723 1H NMR (300 MHz, DMSO) δ 9.55 (s, 1H), 9.09 (d, J = 8.0 Hz,1H), 9.01-8.76 (m, 2H), 8.50 (s, 1H), 8.37 (s, 1H), 8.13-7.91 (m, 4H),7.85 (d, J = 8.9 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.25 (t, J = 7.6 Hz,1H). DMSO 420   (M + 1) 1.89 Method D 100 Meth- od G1 257

HCl 524.39 1H NMR (300 MHz, DMSO) δ 10.68 (s, 1H), 9.50 (s, 1H), 9.08(d, J = 8.1 Hz, 1H), 8.92 (d, J = 5.2 Hz, 1H), 8.28 (s, 1H), 8.11 (s,1H), 8.06-7.93 (m, 2H), 7.87 (d, J = 7.6 Hz, 1H), 7.70-7.51 (m, 2H),7.19 (d, J =7.6 Hz, 1H), 4.28 (t, J = 9.1 Hz, 2H), 4 DMSO 452   (M + 1)1.34 Method D 100 Meth-od G1 258

HCl 474.89 1H NMR (300 MHz, DMSO) δ 10.36 (s, 1H), 9.52 (s, 1H), 9.00(d, J = 8.2 Hz, 1 H), 8.89 (d, J = 4.4 Hz, 1H), 8.12 (s, 1H), 8.02-7.78(m, 4H), 7.64 (d, J = 9.2 Hz, 1H), 7.54 (t, J = 8.2 Hz, 1H), 7.07 (d, J= 7.7 Hz, 1H), 4.08-3.87 (m, 5H), 3.46 (s, 3H). DMSO 439   (M + 1) 2.21Method C  98 Meth- od G1 259

HCl 460.86 1H NMR (300 MHz, DMSO) δ 10.61 (s, 1H), 9.51 (s, 1H), 9.10(d, J = 8.2 Hz, 1H), 8.94 (d, J = 4.9 Hz, 1H), 8.22 (s, 1H), 8.08-7.94(m, 2H), 7.93-7.78 (m, 2H), 7.65 (d, J = 9.1 Hz, 1H), 7.53 (t, J = 8.2Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 4.01 (s, 3H), 3 DMSO 425   (M + 1)1.64 Method C  98 Meth- od G11 260

HCl 429.67 No Data 428.9 (M + 1) 2.35 Method C 100 Meth- od G1 261

HCl 443.24 1H NMR (300 MHz, DMSO) δ 10.35 (s, 1H), 9.52 (d, J = 1.5 Hz,1H), 8.97 (dd, J = 6.6, 1.8 Hz, 2H), 8.91-8.83 (m, 1H), 8.07 (dd, J =8.9, 2.0 Hz, 1H), 7.85 (dd, J = 14 6, 8.2 Hz, 4H), 7.54 (dd, J = 11.7,4.6 Hz, 1H), 7.31 (s, 1H), 7.10-6.99 (m, 1H). DMSO  442.96 (M + 1) 2.36Method C 100 Meth- od G1 262

HCl 426.39 1H NMR (300 MHz, DMSO) δ 10.71 (s, 1H), 9.47 (s, 1H), 9.01(d, J = 8.2 Hz, 1H), 8.90 (d, J = 4.0 Hz, 1H), 8.23 (s, 1H), 8.08-7.86(m, 4H), 7.61 (t, J = 8.2 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 4.28 (d, J= 7.0 Hz, 2H), 1.44 (t, J = 6.9 Hz, 3H). DMSO 427.1 (M + 1) 2.47 MethodC  93 Meth- od G1 263

HCl 446.13 1H NMR (300 MHz, DMSO) δ 10.35 (s, 1H), 9.47 (s, 1H), 8.90(s, 3H), 8.27 (s, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 8.8 Hz, 1H). DMSO 494.0(M + 1) 2.29 Method C  91 Meth- od G1 264

395.46 1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 8.88 (s, 1H), 8.83-8.71(m, 2H), 8.18 (d, J = 9.2 Hz, 1H), 7.30 (dd, J = 9.2, 2.3 Hz, 1H),7.69-7.57 (m, 3H), 7.32 (d, J = 2.1 Hz, 1H), 4.14 (q, J = 6.6 Hz, 2H),2.39 (s, 3H), 2.35 (s, 3H), 1.37 (t, J = 6.9 Hz, 3 DMSO  396.10 (M + 1)2.3 Method C 100 Meth- od G1 265

HCl 469.53 1H NMR (300 MHz, DMSO) δ 12.13 (s, 1H), 9.54 (s, 1H), 8.99(d, J = 7.4 Hz, 1H), 8.85 (s, 2H), 8.61 (d, J = 8.2 Hz, 1H), 7.95 (d, J= 9.1 Hz, 1H), 7.86 (d, J = 7.3 Hz, 2H), 7.68 (dd, J = 15.1, 7.8 Hz,3H), 7.32 (d, J = 6.8 Hz, 1H), 4.00 (s, 3H), 3.71 (d, J DMSO 470.1(M + 1) 2.15 Method C 100 Meth- od G1 266

HCl 455.51 1H NMR (300 MHz, DMSO) δ 12.07 (s, 1H), 9.52 (s, 1H),8.82-8.65 (m, 4H), 7.88 (dd, J = 8.1, 5.0 Hz, 2H), 7.73-7.55 (m, 4H),7.27 (t, J = 7.2 Hz, 1H), 3.98 (m, 1H), 3.82 (d, J = 10.4 Hz, 2H), 3.35(t, J = 11.7 Hz, 2H), 1.68 (d, J = 10.3 Hz, 2H), 1.55- DMSO 456.1(M + 1) 2.09 Method C 100 Meth- od G1 267

HCl 408.36 1H NMR (300 MHz, DMSO) δ 10.57 (s, 1H), 9.45 (d, J = 1.5 Hz,1H), 8.99 (d, J = 8.0 Hz, 1H), 8.89 (d, J = 3.9 Hz, 1H), 8.16 (d, J =2.3 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.94 (t, J = 7.4 Hz, 2H), 7.63(ddd, J = 9.3, 6.9, 2.3 Hz, 2H), 7.52 (d, J = 8.7 Hz, DMSO 409.1 (M + 1)2.3 Method C 100 Meth- od G1 268

HCl 367.4 1H NMR (300 MHz, DMSO) δ 11.12 (s, 1H), 9.81 (s, 1H),9.43-9.37 (m, 1H), 8.58 (ddd, J = 8.0, 4.8, 1.4 Hz, 2H), 8.09 (d, J =2.5 Hz, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J = 7.9Hz, 1H), 7.53-7.41 (m, 3H), 7.17 (t, J = 7.5 Hz, 1H), 7.0 DMSO 368.1(M + 1) 1.98 Method C 100 Meth- od G1 269

386.4 1H NMR (300 MHz, DMSO) δ 11.47 (s, 2H), 9.39 (s, 1H), 8.66 (d, J =2.8 Hz, 1H), 8.56-8.47 (m, 1H), 8.01-7.90 (m, 2H), 7.69-7.55 (m, 2H),7.55-7.40 (m, 2H), 7.05 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H),4.23 (q, J = 6.9 Hz, 2H), 1.44 (t, J = DMSO 387.0 (M + 1) 2.05 Method C100 Meth- od G8 270

407.45 1H NMR (300 MHz, DMSO) δ 10.52 (s, 1H), 9.44 (s, 1H), 8.92 (d, J= 7.4 Hz, 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.46 (d, J = 6.4 Hz, 1H), 8.01(d, J = 8.7 Hz, 2H), 7.92-7.74 (m, 6H), 7.68 (dd, J = 9.2, 2.4 Hz, 1H),7.48 (t, J = 7.8 Hz, 1H), 3.98 (s, 4H). DMSO 408.0 (M + 1) 1.92 Method C100 Meth-od G1, with two drops of conc. HCl 271

HCl 385.42 1H NMR (300 MHz, DMSO) δ 9.75 (s, 1H), 9.66 (s, 1H), 9.39 (s,1H), 8.61 (d, J = 3.1 Hz, 1H), 8.54 (d, J = 8.2 Hz, 1H), 7.85 (s, 1H),7.82 (s, 2H), 7.71 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 9.1 Hz, 1H), 7.46(dd, J = 7.5, 5.2 Hz, 1H), 7.35-7.23 (m, 2H), 3.9 DMSO 386.1 (M + 1)1.79 Method C  96 Meth- od G2 272

HCl 413.47 1H NMR (300 MHz, DMSO) δ 12.30 (s, 1H), 9.57 (d, J = 2.1 Hz,1H), 8.89 (d, J = 8.0 Hz, 1H), 8.77-8.67 (m, 2H), 8.63 (d, J = 7.7 Hz,1H), 7.94-7.83 (m, 2H), 7.71 (t, J = 7.1 Hz, 1H), 7.66-7.52 (m, 3H),7.25 (t, J = 7.4 Hz, 1H), 4.24-4.06 (m, 1H), 3 DMSO 414.2 (M + 1) 2.36Method C 100 Meth- od G1 273

HCl 387.46 1H NMR (300 MHz, DMSO) δ 10.96 (s, 1H), 10.29 (s, 1H), 9.85(s, 1H), 9.51 (d, J = 2.0 Hz, 1H), 8.71-8.62 (m, 2H), 8.47 (dd, J = 8.2,0.9 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.67-7.62 (m, 2H), 7.60 (d, J =2.5 Hz, 1H), 7.57 (d, J = 2.6 Hz, 1H), 7.55-7 DMSO 388.1 (M + 1) 2.01Method C  95 Meth- od G1 274

HCl 399.45 1H NMR (300 MHz, DMSO) δ 12.45 (s, 1H), 9.57 (d, J = 1.3 Hz,1H), 8.96 (dd, J = 8.4, 0.9 Hz, 1H), 8.89 (t, J = 5.2 Hz, 1H) 8.75-8.66(m, 2H), 7.94-7.84 (m, 2H), 7.72 (t, J = 7.9 Hz, 1H), 7.65-7.52 (m, 3H),7.24 (t, J = 7.8 Hz, 1H), 4.00 (s, 3H), 3. DMSO 400.3 (M + 1) 2.21Method C 100 Meth- od G1 275

HCl 453.42 1H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.54 (d, J = 2.0 Hz,1H), 9.40 (t, J = 6.1 Hz, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.73-8.63 (m,2H), 7.89 (d, J = 9.8 Hz, 2H), 7.76 (t, J = 7.1 Hz, 1H), 7.64-7.50 (m,3H), 7.30 (t, J = 7.1 Hz, 1H), 4.16-4.01 (m, 2 DMSO 454.0 (M + 1) 2.28Method C 100 Meth- od G1 276

421.25 1H NMR (300 MHz, DMSO) δ 9.26 (d, J = 2.2 Hz, 1H), 8.71-8.62 (m,2H), 8.46 (dt, J = 8.0, 1.9 Hz, 1H), 8.21 (dd, J = 8.9, 2.3 Hz, 1H),8.03 (d, J = 8.9 Hz, 1H), 7.89 (s, 1H), 7.78 (dd, J = 7.6, 1.6 Hz, 1H),7.72-7.62 (m, 1H), 7.56-7.45 (m, 3H), 7.32 DMSO 423.0 (M + 1) 1.85Method C  94 Meth- od G1 277

HCl 447.49 1H NMR (300 MHz, DMSO) δ 11.25 (s, 1H), 10.46 (s, 1H), 9.45(s, 1H), 8.93 (d, J = 7.9 Hz, 1H), 8.82 (d, J = 3.9 Hz, 1H), 8.22 (d, J= 8.1 Hz, 1H), 7.97-7.79 (m, 4H), 7.73 (t, J = 7.1 Hz, 1H), 7.62 (dd, J= 9.1, 2.5 Hz, 1H), 7.53-7.39 (m, 3H), 7.19 (t, DMSO 448.1 (M + 1) 2.67Method C 100 Meth- od G1 278

HCl 399.45 1H NMR (300 MHz, DMSO) δ 12.59 (s, 1H), 9.57 (d, J = 1.4 Hz,1H), 9.03 (dd, J = 8.4, 0.9 Hz, 1H), 8.91 (d, J = 4.6 Hz, 1H), 8.76-8.64(m, 2H), 7.88 (t, J = 7.8 Hz, 2H), 7.72 (t, J = 7.9 Hz, 1H), 7.63-7.53(m, 3H), 7.22 (td, J = 7.9, 1.1 Hz, 1H), 4.28 DMSO 400.1 (M + 1) 2.5 Method C 100 Meth- od G1 279

HCl 399.45 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.37 (d, J = 1.4 Hz,1H), 8.61 (dd, J = 4.7, 1.7 Hz, 1H), 8.58-8.51 (m, 1H), 7.84 (dd, J =9.0, 5.3 Hz, 3H), 7.65-7.42 (m, 4H), 7.38 (t, J = 7.5 Hz, 1H), 3.95 (s,3H), 2.74 (s, 6H). DMSO 400.1 (M + 1) 2.2  Method C 100 Meth- od G1 280

HCl 439.51 1H NMR (300 MHz, DMSO) δ 12.05 (s, 1H), 9.51 (d, J = 1.6 Hz,1H), 9.04 (d, J = 8.1 Hz, 1H), 8.88 (dd, J = 5.2, 1.3 Hz, 1H), 8.60 (d,J = 7.0 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.00-7.87 (m, 2H), 7.83 (dd,J = 7.8, 1.4 Hz, 1H), 7.77 (d, J = 1.9 Hz, 1H), DMSO 440.1 (M + 1) 2.52Method C 100 Meth- od G1 281

HCl 403.41 1H NMR (300 MHz, DMSO) δ 10.98 (s, 1H), 9.50 (s, 1H),8.72-8.55 (m, 3H), 8.38 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.9 Hz, 1H),7.72-7.45 (m, 4H), 7.19-7.07 (m, 1H), 3.96 (s, J = 5.2 Hz, 3H), 2.73 (d,J = 4.5 Hz, 3H). DMSO 404.1 (M + 1) 2.18 Method C 100 Meth- od G1 282

HCl 417.44 1H NMR (300 MHz, DMSO) δ 10.96 (s, 1H), 9.50 (d, J = 1.9 Hz,1H), 8.71-8.55 (m, 3H), 8.33 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 9.0 Hz,1H), 7.66 (dd, J = 14.8, 8.3 Hz, 1H), 7.60-7.47 (m, 3H), 7.21-7.05 (m,1H), 4.24 (q, J = 6.9 Hz, 2H), 2.73 (d, J = 4. DMSO 419.1 (M + 1) 2.38Method C 100 Meth- od G1 283

HCl 439.39 1H NMR (300 MHz, DMSO) δ 13.10 (s, 1H), 9.68 (d, J = 1.1 Hz,1H), 9.52 (d, J = 1.4 Hz, 1H), 8.75-8.58 (m, 3H), 8.26 (s, 1H), 8.15 (d,J = 8.2 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), 7.59-7.47 (m, 3H), 7.45 (d, J= 2.5 Hz, 1H), 3.95 (s, 3H). DMSO 440.1 (M + 1) 2.25 Method C 100 Meth-od G1 284

HCl 453.42 1H NMR (300 MHz, DMSO) δ 13.08 (s, 1H), 9.70 (s, 1H), 9.55(d, J = 1.3 Hz, 1H), 8.77-8.60 (m, 3H), 8.26 (s, 1H), 8.15 (d, J = 8.5Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.62-7.39 (m, 4H), 4.21 (q, J = 7.1Hz, 2H), 1.45 (t, J = 6.9 Hz, 3H). DMSO 454.1 (M + 1) 2.43 Metho C  95Meth- od G1 285

HCl 410.43 1H NMR (300 MHz, DMSO) δ 12.87 (s, 1H), 9.50 (d, J = 1.5 Hz,2H), 8.73- 8.59 (m, 3H), 8.26 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.85(d, J = 9.1 Hz, 1H), 7.64 (dd, J = 8.1, 1.5 Hz, 1H), 7.59-7.49 (m, 2H),7.42 (d, J = 2.4 Hz, 1H), 4.19 (q, J = 6.9 Hz, 2H DMSO 411.1 (M + 1)2.16 Method C  95 Meth- od G1 286

HCl 397.43 1H NMR (300 MHz, DMSO) δ 13.63 (s, 1H), 9.55 (s, 1H), 9.13(d, J = 8.3 Hz, 1H), 8.75-8.58 (m, 3H), 7.84 (d, J = 9.8 Hz, 1H),7.69-7.48 (m, 4H), 7.01 (d, J = 7.4 Hz, 1H), 3.94 (s, 3H), 3.46-3.36 (m,2H), 2.96 (t, J =- 5.7 Hz, 2H). DMSO 398.3 (M + 1) 2.12 Method C 100Meth- od G1 287

HCl 411.46 1H NMR (300 MHz, DMSO) δ 13.61 (s, 1H), 9.56 (s, 1H), 9.14(d, J = 8.1 Hz, 1H), 8.75- 8.60 (m, 3H), 7.84 (d, J = 9.8 Hz, 1H),7.70-7.46 (m, 4H), 7.02 (d, J = 7.2 Hz, 1H), 4.19 (q, J = 6.9 Hz, 3H),3.48-3.3 (m, 2H),7 2.96 (t, J = 6.1 Hz, 2H), 1.44 (t, DMSO 412.4 (M + 1)2.4  Method C 100 Meth- od G1 288

HCl 383.4 1H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 9.60 (d, J = 1.5 Hz,1H), 9.02 (s, 1H), 8.88 (d, J = 8.0 Hz, 1H), 8.80-8.65 (m, 2H), 7.90 (d,J = 9.0 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.66-7.51 (m, 3H), 7.27 (d, J= 7.6 Hz, 1H), 4.47 (s, 2H), 3.97 (s, 3H). DMSO 384.1 (M + 1) 2.01Method C  95 Meth- od G1 289

HCl 421.4 1H NMR (300 MHz, DMSO) δ 12.07 (s, 1H), 9.48 (d, J = 1.6 Hz,1H), 8.76-8.55 (m, 3H), 8.34 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 9.1 Hz,1H), 7.62-7.49 (m, 2H), 7.38 (d, J = 2.5 Hz, 1H), 7.14 (ddd, J = 11.5,9.0, 2.6 Hz, 1H), 4.19 (q, J = 6.9 Hz, 2H), 1. DMSO 422.2 (M + 1) 2.35Method C 100 Meth- od G1 290

HCl 412.44 1H NMR (300 MHz, DMSO) δ 9.82 (s, 1H), 9.50 (d, J = 2.0 Hz,1H), 8.68-8.58 (m, 2H), 7.98 (d, J = 2.5 Hz, 1H), 7.85 (d, J = 1.8 Hz,1H), 7.80 (d, J = 9.1 Hz, 1H), 7.55-7.43 (m, 3H), 7.23 (d, J = 8.4 Hz,1H), 3.96 (s, 3H), 3.37 (d, J = 4.2 Hz, 6H). DMSO 413.0 (M + 1) 1.79Method C Meth- od G1 291

HCl 426.47 1H NMR (300 MHz, DMSO) δ 9.78 (s, 1H), 9.50 (d, J = 2.0 Hz,1H), 8.68-8.57 (m, 2H), 7.97 (d, J = 2.5 Hz, 1H), 7.85 (d, J = 1.3 Hz,1H), 7.79 (d, J = 9.1 Hz, 1H), 7.55-7.43 (m, 3H), 7.22 (d, J = 8.4 Hz,1H), 4.22 (q, J = 6.9 Hz, 2H), 3.37 (d, J = 4.3 H DMSO 427.1 (M + 1)1.92 Method C Meth- od G1 292

404.39 1H NMR (300 MHz, DMSO) δ 9.36 (d, J = 1.4 Hz, 1H), 8.66 (d, J =2.7 Hz, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 8.9 Hz, 2H), 7.64(d, J = 13.5 Hz, 2H), 7.50 (dd, J = 7.7, 4.2 Hz, 1H), 6.86 (t, J = 6.8Hz, 1H), 6.70 (dd, J = 11.8, 1.7 Hz, 1H), 4.22 (q, DMSO 405.1 (M + 1)1.98 Method C  95 Meth- od G8 293

406.82 1H NMR (300 MHz, DMSO) δ 9.23 (d, J = 1.4 Hz, 1H), 8.63 (d, J =3.6 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.92(s, 1H), 7.81-7.65 (m, 4H), 7.55 (dd, J = 8.4, 2.1 Hz, 1H), 7.48 (dd, J= 6.7, 3.8 Hz, 1H), 7.37 (s, 1H), 3.97 (s, 3H). DMSO 407.1 (M + 1) 1.88Method C 100 Meth- od G8 294

HCl 406.46 1H NMR (300 MHz, DMSO) δ 10.11 (s, 1H), 9.39 (d, J = 1.4 Hz,1H), 8.63 (dd, J = 4.7, 1.7 Hz, 1H), 8.59-8.53 (m, 1H), 8.50 (dd, J =8.2, 0.8 Hz, 1H), 8.03 (dd, J = 8.0, 1.4 Hz, 1H), 7.96-7.84 (m, 2H),7.65-7.46 (m, 4H), 3.94 (s, 3H), 3.25 (s, 3H). DMSO 407.1 (M + 1) 2.13Method C  95 Meth- od G1 Salt Number Starting Material 1 StartingMaterial 2 Product Type 295

296

297

298

299

300

301

302

303

304

305

306

307

308

HCl 309

HCl 310

HCl 311

HCl 312

3 HCl 313

2 HCl 314

HCl 315

HCl 316

317

318

319

320

321

322

323

324

HCl 325

HCl 326

HCl 327

HCl 328

HCl 329

2 HCl 330

HCl 331

2 HCl 332

HCl 333

HCl 334

HCl 335

HCl 336

HCl 337

HCl 338

339

340

341

342

343

344

HCl 345

HCl 346

HCl 347

HCl 348

HCl 349

HCl 350

HCl 351

2 HCl 352

2 HCl 353

HCl 354

HCl 355

HCl 356

HCl 357

HCl 358

HCl 359

HCl 360

HCl 361

HCl 362

HCl 363

HCl 364

2 HCl 365

2 HCl 366

2 HCl 367

2 HCl 368

2 HCl 369

HCl 370

HCl 371

2 HCl 372

2 HCl 373

2 HCl 374

2 HCl 375

2 HCl 376

2 HCl 377

2 HCl 378

2 HCl 379

2 HCl 380

2 HCl 381

HCl 382

HCl 383

2 HCl 384

2 HCl 385

2 HCl 386

2 HCl 387

2 HCl 388

2 HCl 389

2 HCl 390

HCl 391

HCl 392

HCl 393

HCl 394

HCl 395

HCl 396

HCl 397

HCl 398

399

400

2 HCl 401

2 HCl 402

2 HCl 403

2 HCl 404

HCl 405

HCl 406

HCl 407

2 HCl 408

HCl 409

HCl 410

HCl 411

412

HCl 413

Method ¹H NMR Purity of Number ¹H NMR Solvent percent Coupling 295 ¹HNMR (400 MHz, DMSO) δ 13.12 (s, 1H), 9.90 (s, 1H), 9.47 (d, J = 1.4 Hz,1H), 8.70-8.54 (m, 2H), 8.20-8.15 (m, 1H), 8.14 (s, 1H), 8.01 (d, J =2.6 Hz, 1H), 7.88-7.75 (m, 2H), 7.65 (d, J = 8.9 Hz, 1H), 7.59-7.44 (m,2H), 3.98 (s, 3H). DMSO >98 G1 296 ¹H NMR (400 MHz, DMSO) δ 10.04 (s,1H), 9.54-9.47 (m, 1H), 9.36 (s, 1H), 8.72 (d, J = 2.0 Hz, 1H),8.69-8.59 (m, 2H), 8.19 (d, J = 8.8 Hz, 1H), 8.08-7.97 (m, 2H), 7.86 (d,J = 9.1 Hz, 1H), 7.61-7.47 (m, 2H), 3.99 (s, 3H). DMSO >98 G1 297 ¹H NMR(400 MHz, DMSO) δ 9.64 (s, 1H), 9.55-9.45 (m, 1H), 8.72 - 8.60 (rn, 2H),7.95 (d, J = 2.7 Hz, 1H), 7.82 (d, J= 9.1 Hz, 1H), 7.58-7.48 (m, 3H),7.34 (dd, J = 8.7, 2.5 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 4.39-4.23 (m,4H), 3.97 (s, 3H). DMSO >98 G1 298 ¹H NMR (400 MHz, DMSO) δ 11.21 (s,1H), 9.79 (s, 1H), 9.53 (d, J = 1.4 Hz, 1H), 8.75-8.58 (m, 2H), 8.07 (s,1H), 8.03 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.61 (d, J =8.5 Hz, 1H), 7.56-7.47 (m, 2H), 7.43 (dd, J = 8.5, 1.8 Hz, 1H),7.39-7.34 (m, 1H), 6.50-6.41 (m, 1H), 3.99 (s, 3H). DMSO >98 G1 299 ¹HNMR (400 MHz, DMSO) δ 9.54 (s, 1H), 9.42-9.34 (m, 1H), 8.61 (dd, J =4.7, 1.7 Hz, 1H), 8.57-8.47 (m, 1H), 7.93 (d, J = 2.7 Hz, 1H), 7.81 (d,J = 9.1 Hz, 1H), 7.56-7.44 (m, 2H), 7.19 (dd, J = 7.9, 1.5 Hz, 1H),7.00-6.91 (m, 1H), 6.88 (dd, J = 8.2, 1.6 Hz, 1H), 4.34-4.17 (m, 4H),3.95 (s, 3H). DMSO >98 G1 300 ¹H NMR (400 MHz, DMSO) δ 10.76 (s, 1H),10.01 (s, 1H), 9.17-9.06 (m, 1H), 8.53 (dd, J = 4.7, 1.7 Hz, 1H),8.36-8.27 (m, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H),7.60-7.48 (m, 2H), 7.36 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.32-7.28 (m,1H), 7.25 (d, J = 6.8 Hz, 1H), 7.16-7.04 (m, 1H), 6.54 (dd, J = 3.0, 1.9Hz, 1H), 3.98 (s, 3H). DMSO >98 G1 301 ¹H NMR (400 MHz, DMSO) δ 10.02(s, 1H), 9.48 (d, J = 1.5 Hz, 1H), 9.33 (d, J = 1.0 Hz, 1H), 8.69-8.59(m, 2H), 8.37 (d, J = 1.7 Hz, 1H), 8.10 (dd, J = 9.0, 2.1 Hz, 1H), 8.00(d, J = 2.7 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.86 (d, J = 9.1 Hz, 1H),7.57 (dd, J = 9.1, 2.7 Hz, 1H), 7.54-7.47 (m, 1H), 3.99 (s, 3H).DMSO >98 G1 302 ¹H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 9.18 (dd, J =2.2. 0.8 Hz, 1H), 8.60 (dd, J = 4.7, 1.7 Hz, 1H), 8.45-8.36 (m, 1H),8.03 (d, J = 2.7 Hz, 1H), 7.97-7.90 (m, 2H), 7.88 (d, J = 7.0 Hz, 1H),7.77 (dd, J = 9.0, 7.1 Hz, 1H), 7.61 (dd, J = 9.1, 2.7 Hz, 1H), 7.44(ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 4.01 (s, 3H). DMSO >98 G1 303 ¹H NMR(400 MHz, DMSO) δ 9.86 (s, 1H), 9.60-9.56 (rn, 1H), 8.72-8.67 (m, 1H),8.65 (dd, J = 4.8, 1.7 Hz, 1H), 8.26-8.21 (m, 1H), 8.05 (d, J = 2.7 Hz,1H), 7.83 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.56-7.50 (m,2H), 7.46 (dd, J = 8.5, 1.8 Hz, 1H), 7.35 (d, J = 3.1 Hz, 1H), 6.46 (dd,J = 3.1, 0.8 Hz, 1H), 3.99 (s, 3H), 3.86 (s, 3H). DMSO >98 G1 304 ¹H NMR(400 MHz, DMSO) δ.96 (s, 1H), 9.51-9.45 (m, 1H), 8.68-8.59 (m, 2H),8.57-8.52 (m, 1H), 8.02-7.88 (m, 3H), 7.87-7.80 (m, 1H), 7.58-7.46 (m,2H), 3.98 (s, 3H), 2.83 (s, 3H). DMSO >98 G1 305 ¹H NMR (400 MHz, DMSO)δ 9.94 (s, 1H), 9.51-9.43 (rn, 1H), 8.68-8.58 (m, 2H), 8.39 (d, J = 2.0Hz, 1H), 7.99 (d, J = 2.7 Hz, 1H), 7.87-7.80 (m, 2H), 7.78 (d, J = 8.6Hz, 1H), 7.54 (dd, J = 9.1, 2.7 Hz, 1H), 7.51 (ddd, J = 8.0, 4.8, 0.8Hz, 1H), 4.19 (s, 3H), 3.98 (s, 3H). DMSO >98 G1 306 ¹H NMR (400 MHz,DMSO) δ 9.72 (s, 1H), 9.52-9.47 (m, 1H), 8.67-8.60 (m, 2H), 7.98 (d, J =2.7 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.78-7.74 (rn, 1H), 7.68-7.62 (m,1H), 7.55-7.48 (m, 2H), 7.32 (d, J = 8.1 Hz, 1H), 3.97 (s, 3H),2.99-2.88 (m, 4H), 2.15-2.04 (m, 2H). DMSO >98 G1 307 ¹H NMR (400 MHz,CDCl₃) δ 9.74 (s, 1H), 9.37-9.31 (m, 1H), 8.60 (dd, J = 4.7, 1.7 Hz,1H), 8.53-8.46 (m, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 9.1 Hz,1H), 7.52 (dd, J = 9.1, 2.7 Hz, 1H), 7.47 (ddd, J = 8.0, 4.8, 0.8 Hz,1H), 7.34 (d, J = 7.0 Hz, 1H), 7.31-7.24 (m, 1H), 7.22 (d, J = 7.1 Hz,1H), 3.96 (s, 3H), 2.99 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H),2.06-1.96 (m, 2H). DMSO >98 G1 308 ¹H NMR (400 MHz, DMSO) δ 10.45 (s,1H), 9.50-9.44 (m, 1H), 8.94-8.87 (m, 1H), 8.83 (dd, J = 5.1, 1.5 Hz,1H), 8.54 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.02 (d, J =8.7 Hz, 1H), 7.97-7.89 (m, 2H), 7.83 (dd, J = 8.0, 5.2 Hz, 1H), 7.63(dd, J = 9.1, 2.7 Hz, 1H), 4.01 (s, 3H), 2.83 (s, 3H). DMSO >98 G1 309¹H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 9.47 (d, J = 1.5 Hz, 1H), 8.94(d, J = 8.1 Hz, 1H), 8.86 (dd, J = 5.2, 1.5 Hz, 1H), 8.54-8.48 (m, 1H),8.23-8.16 (m, 1H), 8.04-7.94 (m, 2H), 7.92-7.83 (m, 2H), 7.78 (d, J =5.4 Hz, 1H), 7.65 (dd, J = 9.1, 2.6 Hz, 1H), 7.51 (dd, J = 5.4, 0.7 Hz,1H), 4.02 (s, 3H). DMSO >98 G1 310 ¹H NMR (400 MHz, DMSO) δ 10.86 (s,1H), 9.43 (d, J = 1.6 Hz, 1H), 8.94 (d, J = 7.5 Hz, 1H), 8.89 (dd, J =5.2, 1.5 Hz, 1H), 8.30-8.20 (m, 1H), 8.13-7.99 (m, 3H), 7.94-7.84 (m,1H), 7.74 (d, J = 1.3 Hz, 2H), 7.67 (dd, J = 9.1, 2.5 Hz, 1H), 7.08 (d,J = 2.2 Hz, 1H), 4.02 (s, 3H). DMSO >98 G1 311 ¹H NMR (400 MHz, DMSO) δ10.53 (s, 1H), 9.48 (d, J = 1.5 Hz, 1H), 8.93 (d, J = 7.7 Hz, 1H), 8.85(dd, J = 5.2, 1.5 Hz, 1H), 8.44 (d, J = 1.9 Hz, 1H), 8.20-8.15 (m, 1H),8.13 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.92 (dd, J = 8.7,2.0 Hz, 1H), 7.86 (dd, J = 7.8, 5.1 Hz, 1H), 7.64 (dd, J = 9.1, 2.6 Hz,1H), 4.02 (s, 3H), 2.85 (s, 3H). DMSO >98 G1 312 ¹H NMR (400 MHz, DMSO)δ 10.85 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 9.47 (s, 1H), 9.32 (s, 1H),9.03 (d, J = 8.0 Hz, 1H), 8.93-8.87 (m, 1H), 8.86-8.78 (m, 2H), 8.44(dd, J = 8.8, 1.9 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 8.7Hz, 1H), 7.99-7.89 (rn, 2H), 7.78-7.71 (m, 1H), 7.55 (d, J = 8.7 Hz,1H). DMSO >98 G1 313 ¹H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 9.54 (d, J= 1.6 Hz, 1H), 9.51 (d, J = 2.0 Hz, 1H), 9.46-9.39 (rn, 1H), 9.10-9.01(m, 1H), 8.97-8.88 (m, 2H), 8.86 (dd, J = 5.3, 1.3 Hz, 1H), 8.63-8.55(m, 1H), 8.48 (dd, J = 8.8, 1.9 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H),8.04-7.90 (m, 4H), 7.79 (d, J = 5.4 Hz, 1H), 7.52 (dd, J = 5.4, 0.7 Hz,1H). DMSO >98 G1 314 ¹H NMR (400 MHz, DMSO) δ 10.49 (s, 1H), 9.48 (d, J= 1.5 Hz, 1H), 8.93 (d, J = 7.9 Hz, 1H), 8.85 (dd, J = 5.2, 1.5 Hz, 1H),8.24 (s, 1H), 8.16 (d, J = 2.5 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H), 7.96(d, J = 9.1 Hz, 1H), 7.87 (dd, J = 8.1, 5.3 Hz, 1H), 7.77 (d, J = 8.4Hz, 1H), 7.72 (dd, J = 8.4, 1.8 Hz, 1H), 7.64 (dd, J = 9.1, 2.6 Hz, 1H),7.03 (dd, J = 2.2, 1.0 Hz, 1H), 4.02 (s, 3H). DMSO >98 G1 315 ¹H NMR(400 MHz, DMSO) δ 10.72 (s, 1H), 9.46 (d, J = 1.5 Hz, 1H), 8.96 (d, J =8.2 Hz, 1H), 8.87 (dd, J = 5.2, 1.5 Hz, 1H), 8.50 (d, J = 1.8 Hz, 1H),8.21 (d, J = 2.4 Hz, 1H), 8.06-7.96 (rn, 2H), 7.93-7.84 (m, 2H), 7.78(d, J = 5.4 Hz, 1H), 7.63 (dd, J = 9.1, 2.6 Hz, 1H), 7.51 (dd, J = 5.4,0.7 Hz, 1H), 4.29 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H).DMSO >98 G1 316 ¹H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 9.60-9.52 (rn,1H), 8.75-8.63 (m, 2H), 8.16 (d, J = 2.0 Hz, 1H), 8.04-7.95 (m, 2H),7.93-7.83 (m, 2H), 7.63-7.53 (m, 2H), 6.32 (d, J = 1.2 Hz, 1H), 4.01 (s,3H), 2.47 (s, 3H). DMSO >98 G1 (0.1 N HCl added) 317 ¹H NMR (400 MHz,DMSO) δ 11.82 (s, 1H), 10.06 (s, 1H), 9.53-9.46 (m, 1H), 8.81-8.70 (m,2H), 8.04 (d, J = 2.6 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.81 (d, J =2.1 Hz, 1H), 7.67 (dd, J = 7.9, 5.0 Hz, 1H), 7.57 (dd, J = 9.1, 2.7 Hz,1H), 7.53 (dd, J = 8.7, 2.1 Hz, 1H), 7,39 (d, J = 8.6 Hz, 1H), 4.00 (s,3H). DMSO >98 G1 (0.1 N HCl added) 318 ¹H NMR (400 MHz, DMSO) δ 9.89 (s,1H), 9.57-9.48 (m, 1H), 8.72-8.58 (m, 2H), 8.01 (d, J = 2.1 Hz, 1H),7.99 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), 7.59-7.49 (m, 3H),7.43 (d, J = 8.6 Hz, 1H), 3.98 (s, 3H), 3.41 (s, 3H). DMSO >98 G1 (0.1 NHCl added) 319 ¹H NMR (400 MHz, DMSO) δ 9.88 (s 1H), 9.52-9.44 (m, 1H),8.71-8.59 (m, 2H), 8.02-7.91 (m, 2H), 7.83 (d, J = 9.1 Hz, 1H), 7.66(dd, J = 8.4, 2.0 Hz, 1H), 7.58-7.48 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H),3.98 (s, 3H), 3.40 (s, 3H). DMSO >98 G1 (0.1 N HCl added) 320 ¹H NMR(400 MHz, DMSO) δ 10.01 (s, 1H), 9.58-9.51 (m, 1H), 9.45 (s, 1H), 8.75(d, J = 1.9 Hz, 1H), 8.71-8.63 (m, 2H), 8.25 (d, J = 8.7 Hz, 1H),8.08-8.00 (m, 2H), 7.86 (d, J = 9.1 Hz, 1H), 7.61-7.50 (m, 2H), 4.00 (s,3H). DMSO >98 G1 (0.1 N HCl added) 321 ¹H NMR (400 MHz, DMSO) δ 10.43(s, 1H), 9.72 (s, 1H), 9.51-9.45 (m, 1H), 8.67-8.57 (m, 2H), 7.96 (d, J= 2.7 Hz, 1H), 7.81 (d, J = 9.1 Hz, 1H), 7.73-7.68 (m, 1H), 7.64 (dd, J= 8.3, 2.1 Hz, 1H), 7.56-7.48 (m, 2H), 6.93 (d, J = 8.3 Hz, 1H), 3.97(s, 3H), 3.58 (s, 2H). DMSO >98 G1 (0.1 N HCl added) 322 ¹H NMR (400MHz, DMSO) δ 9.95 (s, 1H), 9.54-9.45 (m, 1H), 8.67 (dd, J = 4.7, 1.7 Hz,1H), 8.66-8.60 (m, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 2.6 Hz,1H), 7.89-7.83 (m, 2H), 7.63-7.52 (rn, 3H), 3.98 (s, 3H). DMSO >98 G1(0.1 N HCl added) 323 ¹H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.75 (s,1H), 9.55-9.49 (m, 1H), 8.69- 8.62 (m, 2H), 7.96 (d, J = 2.7 Hz, 1H),7.83 (d, J = 9.1 Hz, 1H), 7.58-7.49 (m, 3H), 7.35 (dd, J = 8.7, 2.5 Hz,1H), 7.06 (d, J = 8.6 Hz, 1H), 4.62 (s, 2H), 3.97 (s, 3H). DMSO >98 G1(0.1 N HCl added) 324 ¹H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 9.58-9.51(m, 1H), 8.92-8.84 (m, 1H), 8.80 (dd, J = 5.0, 1.5 Hz, 1H), 8.16 (d, J =2.0 Hz, 1H), 8.07 (d, J = 2.6 Hz, 1H), 7.98 (dd, J = 8.8, 2.1 Hz, 1H),7.91 (d, J = 9.1 Hz, 1H), 7.83-7.72 (m, 2H), 7.61 (dd, J = 9.1, 2.6 Hz,1H), 6.37 (s, 1H), 4.75 (d, J = 1.2 Hz, 2H), 4.01 (s, 3H), 3.47 (s, 3H).DMSO >98 G1 (0.1 N HCl added) 325 ¹H NMR (400 MHz, DMSO) δ 12.01 (s,1H), 10.15 (s, 1H), 9.58 (d, J = 1.5 Hz, 1H), 8.94-8.86 (m, 1H), 8.78(dd, J = 5.0, 1.5 Hz, 1H), 8.07 (d, J = 2.6 Hz, 1H), 8.04-7.98 (m, 1H),7.91 (dd, J = 9.3, 2.2 Hz, 2H), 7.78-7.69 (m, 2H), 7.66 (dd, J = 8.5,2.0 Hz, 1H), 7.61 (dd, J = 9.1, 2.7 Hz, 1H), 6.44 (d, J = 9.5 Hz, 1H),4.01 (s, 3H). DMSO >98 G1 (0.1 N HCl added) 326 ¹H NMR (400 MHz, DMSO) δ12.19 (s, 1H), 10.21 (s, 1H), 9.58-9.51 (rn, 1H), 8.94-8.86 (m, 1H),8.81 (dd, J = 5.1, 1.6 Hz, 1H), 8.10 (d, J = 2.6 Hz, 1H), 7.96-7.88 (m,2H), 7.79 (dd, J = 7.9, 5.1 Hz, 1H), 7.68-7.56 (rn, 3H). 4.00 (s, 3H).DMSO >98 G1 (0.1 N HCl added) 327 ¹H NMR (400 MHz, DMSO) δ 10.43 (s,1H), 9.57-9.50 (m, 1H), 9.07-8.98 (m, 1H), 8.88 (dd, J = 5.2, 1.4 Hz,1H), 8.16 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 1.9 Hz, 1H), 8.00-7.89 (m,2H), 7.75 (d, J = 8.5 Hz, 1H), 7.67 (dd, J = 8.5, 2.0 Hz, 1H), 7.63 (dd,J = 9.1, 2.6 Hz, 1H), 4.02 (s, 3H), 3.47 (s, 3H). DMSO >98 G1 (0.1 N HCladded) 328 ¹H NMR (400 MHz, DMSO) δ 10.68 (s, 1H), 10.24 (s, 1H), 9.45(d, J = 1.6 Hz, 1H), 9.05-8.95 (m, 1H), 8.92 (dd, J = 5.2, 1.5 Hz, 1H),8.25-8.16 (rn, 1H), 8.09-7.99 (m, 1H), 7.98-7.89 (m, 1H), 7.71-7.60 (m,3H), 6.98 (d, J = 8.3 Hz, 1H), 4.00 (s, 3H), 2.99 (t, J = 7.5 Hz, 2H),2.57-2.52 (m, 2H). DMSO >98 G1 (0.1 N HCl added) 329 ¹H NMR (400 MHz,DMSO) δ 12.05 (s, 1H), 10.98 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 9.32 (s,1H), 9.03 (d, J = 8.2 Hz, 1H), 8.98 (d, J = 1.7 Hz, 1H), 8.92 (dd, J =5.3, 1.4 Hz, 1H), 8.53 (d, J = 2.6 Hz, 1H), 8.46 (dd, J = 8.8, 1.8 Hz,1H), 8.30 (s, 1H), 8.13 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H),7.95 (dd, J = 7.7, 5.3 Hz, 1H), 7.82 (dd, J = 8.6, 2.1 Hz, 1H), 7.26 (d,J = 8.6 Hz, 1H), 4.06 (s, 3H). DMSO >98 G1 (0.1 N HCl added) 330 ¹H NMR(400 MHz, DMSO) δ 10.40 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 9.05-8.97 (m,1H), 8.87 (dd, J = 5.2, 1.5 Hz, 1H), 8.15-8.06 (m, 3H), 8.00-7.87 (m,3H), 7.81 (d, J = 8.5 Hz, 1H), 7.64 (dd, J = 9.1, 2.7 Hz, 1H), 6.43 (d,J = 9.4 Hz, 1H), 4.02 (s, 3H). DMSO >98 G1 (0.1 N HCl added) 331 ¹H NMR(400 MHz, DMSO) δ 12.05 (s, 1H), 10.77 (s, 1H), 9.51 (d, J = 1.5 Hz,1H), 9.43- 9.35 (m, 1H), 9.31-9.21 (m, 1H), 9.04- 8.93 (m, 1H), 8.88(dd, J = 5.2, 1.5 Hz, 1H), 8.81 (dd, J = 5.1, 1.4 Hz, 1H), 8.73 (d, J =8.4 Hz, 1H), 8.42 (dd, J = 8.8, 1.8 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H),8.09 (d, J = 8.7 Hz, 1H), 7.94-7.83 (m, 2H), 7.80 (dd, J = 8.6, 2.2 Hz,1H), 7.27 (d, J = 8.6 Hz, 1H). DMSO >98 G1 (0.1 N HCl added) 332 ¹H NMR(400 MHz, DMSO) δ 10.57 (s, 1H), 9.55 (d, J = 1.6 Hz, 1H), 9.09-9.01(rn, 1H), 8.90 (dd, J = 5.3, 1.5 Hz, 1H), 8.65-8.59 (m, 1H), 8.24-8.16(m, 2H), 8.14 (dd, J = 9.6, 0.8 Hz, 1H), 8.03-7.92 (m, 2H), 7.65 (dd, J= 9.1, 2.7 Hz, 1H), 4.03 (s, 3H). DMSO >98 G1 (0.1 N HCl added) 333 ¹HNMR (400 MHz, DMSO) δ 11.81 (s, 1H), 10.31 (s, 1H), 9.58 (d, J = 1.5 Hz,1H), 9.08 (d, J = 7.9 Hz, 1H), 8.87 (dd, J = 5.2, 1.5 Hz, 1H), 8.13 (d,J = 2.6 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.98-7.88 (m, 2H), 7.81 (d, J= 8.8 Hz, 1H), 7.69 (dd, J = 8.8, 2.1 Hz, 1H), 7.63 (dd, J = 9.1, 2.7Hz, 1H), 6.36 (s, 1H), 4.02 (s, 3H), 2.46 (d, J = 1.1 Hz, 3H). DMSO >98G1 (0.1 N HCl added) 334 ¹H NMR (400 MHz, DMSO) δ 10.51 (s, 1H), 9.53(d, J = 1.6 Hz, 1H), 9.08-9.02 (m, 1H), 8.90 (dd, J = 5.3, 1.5 Hz, 1H),8.63-8.59 (m, 1H), 8.22-8.10 (m, 3H), 8.00-7.92 (m, 2H), 7.63 (dd, J =9.1, 2.6 Hz, 1H), 4.30 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H).DMSO >98 G1 (0.1 N HCl added) 335 ¹H NMR (400 MHz, DMSO) δ 11.99 (s,1H), 10.34 (s, 1H), 9.62-9.52 (m, 1H), 9.11 (d, J = 8.2 Hz, 1H), 8.90(d, J = 4.4 Hz, 1H), 8.13 (d, J = 2.6 Hz, 1H), 8.06 (d, J = 1.8 Hz, 1H),8.00-7.88 (m, 3H), 7.75 (d, J = 8.6 Hz, 1H), 7.68-7.60 (m, 2H), 6.46 (d,J = 9.5 Hz, 1H), 4.29 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H).DMSO >98 G1 (0.1 N HCl added) 336 ¹H NMR (400 MHz, DMSO) δ 11.02 (s,1H), 10.49 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 9.02 (d, J = 8.1 Hz, 1H),8.90 (dd, J = 5.2, 1.5 Hz, 1H), 8.15 (d, J = 2.3 Hz, 1H), 8.00 (d, J =9.1 Hz, 1H), 7.93 (dd, J = 7.8, 5.4 Hz, 1H), 7.63 (dd, J = 9.1, 2.6 Hz,1H), 7.54 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.7, 2.5 Hz, 1H), 7.08 (d,J = 8.6 Hz, 1H), 4.64 (s, 2H), 4.28 (q, J = 6.9 Hz, 2H), 1.45 (t, J =7.0 Hz, 3H). DMSO >98 G1 (0.1 N HCl added) 337 ¹H NMR (400 MHz, DMSO) δ10.36 (s, 1H), 10.25 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 8.98 (d, J = 8.1Hz, 1H), 8.86 (dd, J = 5.2, 1.5 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.94(d, J = 9.1 Hz, 1H), 7.87 (dd, J = 7.7, 5.2 Hz, 1H), 7.61 (dd, J = 9.1,2.6 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.1, 2.1 Hz, 1H),7.28 (d, J = 8.1 Hz, 1H), 4.27 (q, J = 7.0 Hz, 2H), 2.93 (t, J = 7.5 Hz,2H), 2.56-2.52 (m, 2H), 1.45 (t, J = 7.0 Hz, 3H). DMSO >98 G1 (0.1 N HCladded) 338 ¹H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 9.50-9.39 (m, 1H),9.03 (dd, J = 2.1, 0.7 Hz, 1H), 8.52 (dd, J = 4.7, 1.7 Hz, 1H), 8.48 (d,J = 6.0 Hz, 1H), 8.31-8.24 (m, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.12 (d, J= 2.7 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.91-7.78 (rn, 3H), 7.58 (dd, J= 9.1, 2.7 Hz, 1H), 7.35 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 4.01 (s, 3H).DMSO >98 J2 339 ¹H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 9.37 (dd, J =2.1, 0.7 Hz, 1H), 8.62 (dd, J = 4.7, 1.7 Hz, 1H), 8.57-8.49 (m, 1H),7.93 (d, J = 2.7 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.58 (dd, J = 9.1,2.7 Hz, 1H), 7.47 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.40-7.30 (m, 3H),3.98 (s, 3H). DMSO >98 J2 340 ¹H NMR (400 MHz, DMSO) δ 11.31 (s, 1H),9,56 (s, 1H), 9.54 (dd, J = 2.1, 0.7 Hz, 1H), 8.80-8.66 (rn, 2H), 8.14(d, J = 9.2 Hz, 1H), 7.77 (dd, J = 9.2, 2.8 Hz, 1H), 7.58 (ddd, J = 8.0,4.8, 0.8 Hz, 1H), 7.36 (d, J = 2.8 Hz, 1H), 7.03-6.94 (m, 1H), 6.68 (dd,J = 7.3, 0.8 Hz, 1H), 6.56 (dd, J = 8.2, 0.8 Hz, 1H), 3.86 (s, 3H).DMSO >98 J2 341 ¹H NMR (400 MHz, DMSO) δ 10.00 (s, 1H), 9.54-9.49 (m,1H), 8.75 (s, 1H), 8.69-8.62 (m, 2H), 8.50 (d, J = 1.7 Hz, 1H), 8.02 (d,J = 2.7 Hz, 1H), 7.91-7.85 (m, 2H), 7.83 (dd, J = 8.6, 1.9 Hz, 1H),7.60-7.51 (m, 2H), 4.00 (s, 3H). DMSO >98 J2 342 ¹H NMR (400 MHz, DMSO)δ 10.08 (s, 1H), 9.34-9.27 (m, 1H), 8.60 (dd, J = 4.7, 1.7 Hz, 1H),8.51-8.44 (rn, 1H), 7.94 (d, J = 2.7 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H),7.58 (dd, J = 9.1, 2.7 Hz, 1H), 7.56=7.51 (m, 1H), 7.51-7.47 (m, 2H),7.45 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 3.98 (s, 3H). DMSO >98 J2 343 ¹HNMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.93 (s, 1H), 9.26 (d, J = 1.4 Hz,1H), 8.59 (dd, J = 4.8, 1.7 Hz, 1H), 8.50-8.43 (m, 1H), 8.01 (d, J = 2.7Hz, 1H), 7.98 (d, J = 9.5 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), 7.65 (d, J= 8.4 Hz, 1H), 7.55 (dd, J = 9.1, 2.7 Hz, 1H), 7.49-7.42 (m, 1H), 7.36(d, J = 8.3 Hz, 1H), 6.55 (dd, J = 9.5, 1.7 Hz, 1H), 3.98 (s, 3H), 2.33(s, 3H). DMSO >98 J2 344 ¹H NMR (400 MHz, DMSO) δ 9.34-9.28 (m, 1H),8.81-8.75 (m, 1H), 8.74-8.65 (m, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.93 (d,J = 2.7 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.80-7.72 (m, 2H), 7.69 (d, J= 2.8 Hz, 1H), 7.59 (dd, J = 8.8, 2.7 Hz, 1H), 4.00 (s, 3H). DMSO >98 G8using DMF instead of THF 345 ¹H NMR (400 MHz, DMSO) δ 9.35-9.29 (m, 1H),8.87-8.78 (m, 2H), 8.19 (d, J = 9.4 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H),7.94 (d, J = 8.5 Hz, 1H), 7.86 (dd, J = 8.0, 5.3 Hz, 1H), 7.77 (dd, J =9.1, 2.9 Hz, 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H),7.54 (dd, J = 8.5, 2.3 Hz, 1H), 6.56 (d, J = 9.6 Hz, 1H), 4.02 (s, 3H).DMSO >98 G12 at room tempera-ture 346 ¹H NMR (400 MHz, DMSO) δ 11.98 (s,1H), 9.29 (d, J = 1.7 Hz, 1H), 8.88-8.87 (m, 2H), 8.08 (d, J = 9.2 Hz,1H), 7.97 (d, J = 9.6 Hz, 1H), 7.88 (dd, J = 8.1, 5.4 Hz, 1H), 7.81 (d,J = 2.6 Hz, 1H), 7.78-7.72 (m, 2H), 7.67 (dd, J = 8.9, 2.6 Hz, 1H), 7.48(d, J = 8.9 Hz, 1H), 6.60 (d, J = 9.5 Hz, 1H), 4.02 (s, 3H). DMSO >98G12 at room tempera-ture 347 ¹H NMR (400 MHz, DMSO) δ 9.33-9.28 (m, 1H),8.87-8.67 (m, 2H), 8.06 (d, J = 9.1 Hz, 1H), 7.91-7.79 (m, 1H), 7.75(dd, J = 9.1, 2.9 Hz, 1H), 7.71 (d, J = 2.8 Hz, 1H), 7.67-7.61 (m, 2H),7.58-7.51 (m, 2H), 4.01 (s, 3H). DMSO >98 G12 at room tempera-ture 348¹H NMR (400 MHz, DMSO) δ 9.28 (d, J = 2.0 Hz, 1H), 8.85-8.67 (m, 2H),8.06 (d, J = 9.0 Hz, 1H), 7.88-7.77 (m, 1H), 7.77-7.69 (m, 2H),7.62-7.54 (m, 2H), 7.51-7.45 (m, 2H), 7.44-7.37 (m, 1H), 4.02 (d, J =3.9 Hz, 3H). DMSO >98 G12 at room tempera-ture 349 ¹H NMR (400 MHz,DMSO) δ 9.23 (dd, J = 2.1, 0.7 Hz, 1H), 8.80 (dd, J = 5.2, 1.6 Hz, 1H),8.72-8.64 (m, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.84-7.71 (m, 4H), 7.66(dd, J = 8.1, 1.6 Hz, 1H), 7.61-7.54 (m, 1H), 7.52-7.45 (m, 1H), 4.02(s, 3H). DMSO >98 G12 at room tempera-ture 350 ¹H NMR (400 MHz, DMSO) δ9.22 (d, J = 1.7 Hz, 1H), 8.87-8.79 (m, 1H), 8.77-8.67 (m, 1H), 8.06 (d,J = 9.2 Hz, 1H), 7.92-7.79 (m, 1H), 7.74 (dd, J = 9.1, 2.9 Hz, 1H), 7.70(d, J = 2.8 Hz, 1H), 7.45-7.37 (m, 2H), 7.33-7.27 (m, 1H), 7.17-7.09 (m,1H), 4.01 (s, 3H), 3.71 (s, 3H). DMSO >98 G12 at room tempera-ture 351¹H NMR (400 MHz, DMSO) δ 12.03 (s, 1H), 10.69 (s, 1H), 9.65 (d, J = 1.8Hz, 1H), 9.26-9.21 (m, 1H), 9.20-9.12 (m, 1H), 8.99-8.88 (m, 2H), 8.52(d, J = 2.6 Hz, 1H), 8.49-8.42 (m, 1H), 8.25-8.17 (m, 1H), 8.15-8.08 (m,2H), 8.02-7.96 (m, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.77 (d, J = 8.5 Hz,1H), 7.72 (dd, J = 8.5, 1.9 Hz, 1H), 6.47 (d, J = 9.6 Hz, 1H), 4.04 (s,3H). DMSO >98 G1 352 ¹H NMR (400 MHz, DMSO) δ 12.04 (s, 1H), 10.92 (s,1H), 9.65 (d, J = 1.7 Hz, 1H), 9.58-9.50 (m, 1H), 9.46-9.39 (m, 1H),9.27-9.18 (m, 1H), 9.01-8.92 (m, 2H), 8.88 (dd, J = 5.3, 1.2 Hz, 1H),8.48 (dd, J = 8.8, 1.9 Hz, 1H), 8.20-8.10 (m, 2H), 8.09-8.01 (m, 2H),7.93 (d, J = 9.5 Hz, 1H), 7.81-7.72 (m, 2H), 6.47 (d, J = 9.5 Hz, 1H).DMSO >98 G1 353 1H NMR (300 MHz, DMSO) δ 10.90 (s, 1H), 9.63 (s, 1H),.8.89 (d, J = 8.0 Hz, 1H), 8.76 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 2.1 Hz,1H), 7.89 (d, J = 9.1 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H) 7.78-7.65 (m,2H), 7.63-7.49 (m, 2H), 7.47-7.33 (m, 2H), 3.98 (s, 3H). DMSO >98 G1 3541H NMR (300 MHz, DMSO) δ 11.44 (s, 1H), 9.58 (d, J = 1.8 Hz, 1H), 9.16(d, J = 8.2 Hz, 1H), 8.96 (dd, J = 5.3, 1.3 Hz, 1H), 8.29 (d, J = 2.5Hz, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.99 (dd, J = 8.0, 5.4 Hz, 1H),7.72-7.49 (m, 2H), 7.44-7.27 (m, 3H), 7.12 (s, 1H), 3.99 (s, 3H), 2.52(s, 3H). DMSO >98 G1 355 1H NMR (300 MHz, DMSO) δ 11.38 (s, 1H), 9.53(s, 1H), 9.18 (d, J = 8.1 Hz, 1H), 8.97 (d, J = 5.3 Hz, 1H), 8.21 (s,1H), 8.14-8.02 (m, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 9.1 Hz,1H), 6.90 (s, 1H), 3.99 (s, 3H). DMSO >98 G1 356 1H NMR (300 MHz, DMSO)δ 11.30 (s, 1H), 9.59 (d, J = 1.8 Hz, 1H), 9.19 (d, J = 8.2 Hz, 1H),8.97 (dd, J = 5.3, 1.2 Hz, 1H), 8.24 (d, J = 2.5 Hz, 1H), 8.11-7.93 (m,2H), 7.76-7.54 (m, 4H), 7.40 (t, J = 7.6 Hz, 1H), 7.26 (s, 1H), 7.21 (d,J = 7.4 Hz, 1H), 3.98 (s, 3H), 2.41 (s, 3H). DMSO >98 G1 357 1H NMR (300MHz, DMSO) δ 11.21 (s, 1H), 9.59 (d, J = 1.7 Hz, 1H), 9.22 (d, J = 8.1Hz, 1H), 9.02-8.95 (m, 1H), 8.23 (d, J = 2.5 Hz, 1H), 8 13-7.96 (m, 3H),7.85 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.60 (dd, J = 9.1,2.6 Hz, 1H), 7.31 (s, 1H), 3.98 (s, 3H). DMSO >98 G1 358 1H NMR (300MHz, DMSO) δ 10.87 (s, 1H), 9.65-9.55 (m, 1H), 8.93 (dt, J = 8.0, 1.8Hz, 1H), 8.81 (dd, J = 5.0, 1.6 Hz, 1H), 8.18 (d, J = 2.6 Hz, 1H),7.94-7.,82 (m, 4H), 7.78 (dd, J = 8.0, 5.0 Hz, 1H), 7.60-7.46 (m, 4H),.44-7.35 (m, 1H), 7.32 (s, 1H), 3.98 (s, 3H). DMSO >98 G1 359 H NMR (300MHz, DMSO) δ 11.29 (s, 1H), 9.59 (s, 1H), 9.20 (d, J = 8.1 Hz, 1H),9.01-8.94 (m, 1H), 8.25 (s, 1H), 8.12- 7.98 (m, 2H), 7.90-7.75 (m, 2H),7.62 (d, J = 9.1 Hz, 1H), 7.21 (s, 1H), 7.08 (d, J = 8.6 Hz, 2H), 3.99(s, 3H), 3.84 (s, 3H). DMSO >98 G1 360 1H NMR (300 MHz, DMSO) δ 11.29(s, 1H), 9.60 (s, 1H), 9.21 (d, J = 8.0 Hz, 1H), 8.99 (d, J = 5.3 Hz,1H), 8.26 (d, J = 2.2 Hz, 1H), 8.11-7.99 (m, 2H), 7.77 (d, J = 8.0 Hz,2H), 7.62 (dd, J = 9.1, 2.4 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.26 (s,1H), 3.99 (s, 3H), 2.37 (s, 3H). DMSO >98 G1 361 1H NMR (300 MHz, DMSO)δ 11.00 (s, 1H), 9.55 (d, J = 1.7 Hz, 1H), 8.96 (dt, J = 8.1, 1.7 Hz,1H), 8.86 (dd, J = 5.1, 1.5 Hz, 1H), 8.19 (d, J = 2.6 Hz, 1H), 7.97 (d,J = 9.2 Hz, 1H), 7.83 (dt, J = 9.5, 4.8 Hz, 1H), 7.55 (dd, J = 9.1, 2.6Hz, 1H), 6.72 (s, 1H), 3.95 (d, J = 7.0 Hz, 3H), 2.35 (d, J = 3.5 Hz,3H). DMSO >98 G1 362 H NMR (300 MHz, DMSO) δ 11.21 (s, 1H), 9.58 (d, J =1.5 Hz, 1H), 9.21-9.06 (m, 1H), 8.95 (d, J = 4.3 Hz, 1H), 8.22 (d, J =2.3 Hz, 1H), 8.09-7.92 (m, 2H), 7.70-7.51 (m, 3H), 7.24-7.17 (m, 1H),7.13 (s, 1H), 3.99 (s, 3H). DMSO >98 G1 363 1H NMR (300 MHz, DMSO) δ11.07 (s, 1H), 9.60 (s, 1H), 9.13 (d, J = 6.5 Hz, 1H), 8.93 (d, J = 5.1Hz, 1H), 8.23 (s, 1H), 8.05-7.85 (m, 4H), 7.67-7.54 (m, 1H), 7.43-7.23(m, 3H), 3.99 (s, 3H). DMSO >98 G1 364 1H NMR (300 MHz, DMSO) δ 11.16(s, 1H), 9.57 (d, J = 1.5 Hz, 1H), 9.14 (d, J = 8.1 Hz, 1H), 8.93 (d, J= 5.2 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 8.03-7.89 (rn, 4H), 7.61-7.54(m, 2H), 7.32 (s, 1H), 3.97 (s, 3H). DMSO >98 G1 365 1H NMR (300 MHz,DMSO) δ 11.29 (s, 1H), 9.58 (d, J = 1.6 Hz,. 1H), 9.27 (d, J = 8.2 Hz,1H), 9.06- 8.99 (m, 1H), 8.18 (d, J = 2.5 Hz, 1H), 8.10 (dd, J = 8.1,5.5 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.91 (dd, J = 10.7, 1.8 Hz, 1H),7.80-7.65 (m, 2H), 7.57 (dd, J = 9.1, 2.6 Hz, 1H), 7.29 (s, 1H), 3.96(s, 3H). DMSO >98 G1 366 1H NMR (300 MHz, DMSO) δ 11.17 (s, 1H), 9.60(s, 1H), 9.24 (d, J = 8.2 Hz, 1H), 8.98 (d, J = 5.1 Hz, 1H), 8.22 (d, J= 2.5 Hz, 1H), 8.11-8.04 (m, 1H), 8.02-7.91 (m, 2H), 7.82-7.68 (m, 2H),7.62 (dd, J = 9.1, 2.5 Hz, 1H), 7.36 (s, 1H), 4.01 (d, J = 11.0 Hz, 3H).DMSO >98 G1 367 1H NMR (300 MHz, DMSO) δ 11.53 (s, 1H), 9.58 (d, J = 1.8Hz, 1H), 9.20 (d, J = 8.2 Hz, 1H), 8.98 (dd, J = 5.3, 1.3 Hz, 1H), 8.25(d, J = 2.5 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 8.04-7.95 (rn, 1H),7.80-7.68 (rn, 2H), 7.63-7.57 (rn, 1H), 7.56-7.48 (rn, 1H), 7.31 (s,1H), 3.99 (d, J = 6.7 Hz, 3H). DMSO >98 G1 368 1H NMR (300 MHz, DMSO) δ11.24 (s, 1H), 9.59 (d, J = 1.7 Hz, 1H), 9.26 (d, J = 8.3 Hz, 1H), 9.00(d, J = 4.2 Hz, 1H), 8.23 (d, J = 2.6 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H),8.09 (dd, J = 8.1, 5.4 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.91 (dd, J =8.4, 2.1 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 9.1, 2.5 Hz,1H), 7.37 (s, 1H), 3.98 (s, 3H). DMSO >98 G1 369 1H NMR (300 MHz, DMSO)δ 11.33 (s, 1H), 9.62 (s, 1H), 9.27 (d, J = 8.4 Hz, 1H), 9.01 (d, J =5.2 Hz, 1H), 8.29-8.19 (m, 3H), 8.13-8.01 (m, 2H), 7.79-7.73 (m, 2H),7.63 (dd, J = 9.1, 2.6 Hz, 1H), 7.42 (s, 1H), 3.99 (s, 3H). DMSO >98 G1370 1H NMR (300 MHz, DMSO) δ 11.31 (s, 1H), 9.55 (d, J = 1.7 Hz, 1H),9.07 (d, J = 7.9 Hz, 1H), 8.92 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 2.5 Hz,1H), 8.04 (d, J = 9.1 Hz, 1H), 7.98-7.68 (m, 5H), 7.63 (dd, J = 9.2, 2.5Hz, 1H), 7.13 (s, 1H), 4.00 (s, 3H). DMSO >98 G1 371 1H NMR (300 MHz,CDCl3) δ 11.29 (s, 1H), 9.57 (d, J = 1.8 Hz, 1H), 9.07 (d, J = 8.1 Hz,1H), 8.93 (dd, J = 5.2, 1.3 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 8.07-7.97(m, 2H), 7.92 (dd, J = 8.0, 5.3 Hz, 1H), 7.67-7.51 (m, 4H), 7.28 (s,1H), 3.99 (s, 3H). DMSO >98 G1 372 1H NMR (300 MHz, DMSO) δ 11.32 (s,1H), 9.60 (d, J = 1.7 Hz, 1H), 9.27 (d, J = 8.1 Hz, 1H), 9.03 (d, J =5.4 Hz, 1H), 8.22 (d, J = 2.5 Hz, 1H), 8.12 (dd, J = 8.1, 5.7 Hz, 1H),8.03 (d, J = 8.8 Hz, 3H), 7.59 (dd, J = 9.1, 2.5 Hz, 1H), 7.52 (d, J =8.1 Hz, 2H), 7.32 (s, 1H), 3.98 (d, J = 6.7 Hz, 3H). DMSO >98 G1 373 1HNMR (300 MHz, DMSO) δ 11.38 (s, 1H), 9.61 (d, J = 1.6 Hz, 1H), 9.26 (d,J = 8.2 Hz, 1H), 9.02 (d, J = 5.3 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H),8.12-8.01 (m, 2H), 7.95 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.71-7.56 (m,2H), 7.45-7.33 (m, 2H), 4.10-3.90 (m, 3H). DMSO >98 G1 374 1H NMR (300MHz, DMSO) δ 11.29 (s, 1H), 9.56 (s, 1H), 9.12 (d, J = 7.7 Hz, 1H), 8.94(d, J = 4.9 Hz, 1H), 8.26 (d, J = 2.3 Hz, 1H), 8.07-7.90 (m, 2H),7.71-7.57 (m, 2H), 7.51 (s, 1H), 7.47-7.37 (m, 1H), 7.17 (s, 1H), 3.99(s, 3H), 2.53 (s, 3H). DMSO >98 G1 375 1H NMR (300 MHz, DMSO) δ13.13-11.88 (m, 1H), 9.66 (d, J = 1.4 Hz, 1H), 9.36 (d, J = 8.2 Hz, 1H),9.00 (d, J = 5.4 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.14 (dd, J = 8.1,5.6 Hz, 1H), 8.01 (d, J = 7.5 Hz, 2H), 7.89 (d, J = 9.1 Hz, 1H), 7.78(s, 1H), 7.64-7.35 (m, 9H), 5.23 (s, 2H). DMSO >98 J NaOtBu, Pd(OAc)2,Tri-t-butyl- phos- phonium tetrafluoro- borate, Toluene 376 1H NMR (300MHz, DMSO) δ 12.49 (s, 1H), 9.63 (s, 1H), 9.27 (d, J = 8.1 Hz, 1H), 8.96(d, J = 5.4 Hz, 1H), 8.34 (s, 1H), 8.07 (dd, J = 8.1, 5.6 Hz, 1H), 7.99(d, J = 3.3 Hz, 2H), 7.85 (d, J = 9.1 Hz, 1H), 7.80 (s, 1H), 7.64-7.35(m, 9H), 5.21 (s, 2H). DMSO >98 J NaOtBu, Pd(OAc)2, Tri-t-butyl- phos-phonium tetrafluoro- borate, Toluene 377 1H NMR (300 MHz, DMSO) δ 9.56(d, J = 1.8 Hz, 1H), 9.30-9.21 (m, 1H), 9.01 (dd, J = 5.5, 1.2 Hz, 1H),8.18-8.03 (m, 2H), 7.76-7.64 (m, 2H), 7.55-7.45 (m, 2H), 7.33 (dd, J =8.6, 2.3 Hz, 1H), 4.69 (t, J = 7.9 Hz, 2H), 3.92 (s, 3H), 3.26 (t, J =7.8 Hz, 2H). DMSO >98 G8 378 1H NMR (300 MHz, DMSO) δ 9.54 (d, J = 1.9Hz, 1H), 8.70-8.65 (m, 2H), 7.95 (d, J = 9.2 Hz, 1H), 7.66-7.50 (m, 2H),7.45-7.36 (m, 2H), 7.27 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H),4.61 (t, J = 8.1 Hz, 2H), 3.87 (s, 3H), 3.38-3.17 (m, 5H). DMSO >98 G8at 50° C. 379 1H NMR (400 MHz, DMSO) δ 9.54 (d, J = 1.9 Hz, 1H),9.28-9.18 (m, 1H), 8.99 (dd, J = 5.5, 1.3 Hz, 1H), 8.18-8.02 (m, 2H),7.69 (dd, J = 9.2, 2.7 Hz, 1H), 7.58-7.46 (m, 2H), 7.39 (dd, J = 8.2,5.9 Hz, 1H), 6.96-6.85 (m, 1H), 4.71 (t, J = 8.0 Hz, 2H), 3.92 (s, 3H),3.22 (t, J = 7.8 Hz, 2H). DMSO >98 G8 at 50° C. 380 1H NMR (300 MHz,DMSO) δ 9.55 (d, J = 1.8 Hz, 1H), 9.11 (d, J = 8.1 Hz, 1H), 8.93 (dd, J= 5.3, 1.4 Hz, 1H), 8.10-7.93 (m, 2H), 7.76 (dd, J = 8.7, 4.7 Hz, 1H),7.67 (dd, J = 9.2, 2.6 Hz, 1H), 7.52 (d, J = 2.6 Hz, 1H), 7.28 (dd, J =8.4, 2.6 Hz, 1H), 7.12 (td, J = 9.0, 2.7 Hz, 1H), 4.70 (t, J = 7.9 Hz,2H), 3.92 (s, 3H), 3.26 (t, J = 7.5 Hz, 2H). DMSO >98 G8 at 50° C. 3811H NMR (300 MHz, DMSO) δ 9.66 (d, J = 2.0 Hz, 1H), 9.15-9.06 (m, 1H),8.91 (dd, J = 5.2. 1.5 Hz, 1H), 8.27-8.17 (m, 2H), 8.01 (d, J = 8.9 Hz,1H), 7.94 (dd, J = 8.2, 5.2 Hz, 1H), 7.88-7.78 (m, 2H), 7.42 (d, J = 2.7Hz, 1H), 7.35 (dd, J = 8.8, 2.2 Hz, 1H), 6.96 (d, J = 3.5 Hz, 1H), 3.91(s, 3H). DMSO >98 G8 at 50° C. 382 1H NMR (300 MHz, DMSO) δ 9.56 (d, J =1.6 Hz, 1H), 9.26 (d, J = 8.2 Hz, 1H), 9.05-8.98 (m, 1H), 8.20-8.02 (m,2H), 7.69 (dd, J = 9.2, 2.7 Hz, 1H), 7.53-7.40 (m, 2H), 7.32 (dd, J =14.0, 8.0 Hz, 1H), 6.92 (t, J = 8.5 Hz, 1H), 4.71 (t, J = 7.9 Hz, 2H),3.91 (s, 3H), 3.28 (t, J = 7.8 Hz, 2H). DMSO >98 G8 at 50° C. 383 1H NMR(300 MHz, DMSO) δ 9.66 (d, J = 1.5 Hz, 1H), 9.23-9.09 (m, 1H), 8.93 (dd,J = 5.3, 1.5 Hz, 1H), 8.31-8.16 (m, 2H), 8.08-7.93 (m, 2H), 7.82 (dd, J= 9.2, 2.8 Hz, 1H), 7.56 (dd, J = 9.4, 2.5 Hz, 1H), 7.43 (d, J = 2.7 Hz,1H), 7.19 (td, J = 9.2, 2.7 Hz, 1H), 7.02-6.89 (m, 1H), 3.91 (s, 3H).DMSO >98 G8 at 50° C. 384 1H NMR (300 MHz, DMSO) δ 9.66 (d, J = 1.6 Hz,1H), 9.23- 9.09 (m, 1H), 8.94 (dd, J = 5.3, 1.5 Hz, 1H), 8.26-8.14 (m,2H), 8.00 (dd, J = 8.1, 5.3 Hz, 1H), 7.90-7.73 (m, 3H), 7.45 (d, J = 2.7Hz, 1H), 7.25-7.10 (m, 1H), 6.98 (d, J = 3.5 Hz, 1H), 3.92 (s, 3H).DMSO >98 G8 at 50° C. 385 1H NMR (300 MHz, DMSO) δ 9.54 (d, J = 1.8 Hz,1H), 9.21 (dt, J = 8.2, 1.6 Hz, 1H), 8.98 (dd, J = 5.5, 1.3 Hz, 1H),8.20-8.00 (m, 2H), 7.68 (dd, J = 9.2, 2.7 Hz, 1H), 7.55-7.31 (m, 3H),7.00-6.78 (m, 1H), 4.69 (t, J = 7.9 Hz, 2H), 4.19 (q, J = 7.0 Hz, 2H),3.22 (t, J = 7.9 Hz, 2H), 1.41 (t, J = 6.9 Hz, 3H). DMSO >98 G8 at 50°C. 386 1H NMR (300 MHz, DMSO) δ 9.42 (d, J = 1.5 Hz, 1H), 9.06 (d, J =8.1 Hz, 1H), 8.93 (d, J = 5.4 Hz, 1H), 8.09-7.99 (m, 2H), 7.68 (dd, J =9.1, 2.7 Hz, 1H), 7.53 (d, J = 2.6 Hz, 1H), 7.30-7.16 (m, 3H), 4.66 (t,J = 7.9 Hz, 2H), 3.98 (s, 3H), 3.29 (t, J = 7.7 Hz, 2H). DMSO >98 G8 at50° C. 387 1H NMR (300 MHz, DMSO) δ 9.37 (d, J = 1.4 Hz, 1H), 9.11 (d, J= 8.2 Hz, 1H), 8.99 (d, J = 4.9 Hz, 1H), 8.14 (dd, J = 8.2, 5.6 Hz, 1H),8.06 (d, J = 9.2 Hz, 1H), 7.70 (dd, J = 9.2, 2.6 Hz, 1H), 7.51 (d, J =2.7 Hz, 1H), 7.45-7.36 (m, 2H), 7.26-7.15 (m, 1H), 4.83 (d, J = 9.5 Hz,1H), 4.49- 4.38 (m, 2H), 4.00 (s, 3H), 3.48-3.28 (m, 1H), 3.27-3.05 (m,1H). DMSO >98 G8 at 50° C. 388 1H NMR (400 MHz, DMSO) δ 9.56 (d, J = 1.9Hz, 1H), 9.31-9.19 (m, 1H), 9.00 (dd, J = 5.5, 1.3 Hz, 1H), 8.21-8.02(rn, 2H), 7.73-7.64 (m, 2H), 7.47 (dd, J = 5.4, 2.4 Hz, 2H), 7.32 (dd, J= 8.6, 2.3 Hz, 1H), 4.67 (t, J = 8.0 Hz, 2H), 4.18 (q, J = 7.0 Hz, 2H),3.26 (t, J = 7.8 Hz, 2H), 1.41 (t, J = 6.9 Hz, 3H). DMSO >98 G8 at 50°C. 389 1H NMR (400 MHz, DMSO) δ 9.54 (d, J = 1.8 Hz, 1H), 9.25 (dt, J =8.2, 1.6 Hz, 1H), 9.04 (dd, J = 5.5, 1.1 Hz, 1H), 8.26 (d, J = 2.1 Hz,1H), 8.16 (dd, J = 8.0, 5.6 Hz, 1H), 8.11-7.96 (m, 2H), 7.91 (d, J = 8.6Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.6, 2.3 Hz, 1H), 4.68(t, J = 7.9 Hz, 2H), 3.25 (t, J = 7.8 Hz, 2H). DMSO >98 G8 at 50° C. 390¹H NMR (400 MHz, DMSO) δ 9.37 (d, J = 1.4 Hz, 1H), 8.82 (dd, J = 5.1,1.5 Hz, 1H), 8.76 {dd, J = 8.1 Hz, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.46(dd, J = 8.8, 2.1 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.91 (dd, J = 6.3,2.6 Hz, 1H), 7.80 (dd, J = 8.0, 5.1 Hz, 1H), 7.71-7.59 (m, 2H),7.52-7.38 (m, 3H), 7.10-7.01 (m, 1H), 3.89 (s, 3H). DMSO >98 G8 with DMFinstead of THF 391 1H NMR (400 MHz, DMSO) δ 9.383 (d, J = 1.4 Hz, 1H),8.82 (d, J = 5.1 Hz, 1H), 8.76 (d, J = 7.9 Hz, 1H), 8.63 (d, J = 1.8 Hz,1H), 8.46 (dd, J = 8.8, 2.2 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.97 (d,J = 2.7 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.84-7.76 (m, 1H), 7.64 (dd,J = 8.8, 2.7 Hz, 1H), 7.52-7.39 (m, 3H), 7.10- 7.02 (m, 1H), 3.88 (s,3H). DMSO >98 G8 with DMF instead of THF 392 ¹H NMR (400 MHz, DMSO) δ9.39 (t, J = 3.2 Hz, 1H), 8.93-8.82 (m, 2H), 8.62 (d, J = 1.8 Hz, 1H),8.47 (dd, J = 8.8, 2.2 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.91 (dd, J =8.1, 5.3 Hz, 1H), 7.84- 7.77 (m, 1H), 7.73-7.63 (m, 1H), 7.53-7.40 (m,4H), 7.09-7.03 (m, 1H), 3.87 (d, J = 6.5 Hz, 3H). DMSO >98 G8 with DMFinstead of THF 393 ¹H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 11.10 (s,1H), 9.42 (d, J = 1.9 Hz, 1H), 8.90-8.69 (m, 2H), 8.62 (d, J = 1.7 Hz,1H), 8.40 (dd, J = 8.8, 1.9 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 7.92 (d,J = 7.7 Hz, 1H), 7.84-7.69 (m, 1H), 7.57-7.40 (m, 3H), 7.11- 7.02 (m,2H), 6.96 (d, J = 8.3 Hz, 1H), 3.89 (s, 3H). DMSO >98 G8 with DMFinstead of THF 394 ¹H NMR (400 MHz, DMSO) δ 9.43-9.29 (m, 1H), 8.75-8.64(m, 2H), 8.60-8.48 (m, 1H), 8.47-8.32 (m, 1H), 8.21-8.01 (m, 2H),7.86-7.74 (m, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.59-7.34 (m, 4H),7.13-7.01 (m, 1H), 6.87 (d, J = 8.7 Hz, 1H), 3.90 (t, J = 5.3 Hz, 3H).DMSO >98 G8 with DMF instead of THF 395 ¹H NMR (400 MHz, DMSO) δ 9.24(dd, J = 2.2, 0.8 Hz, 1H), 8.76 (dd, J = 5.0, 1.7 Hz, 1H), 8.61-8.54 (m,1H), 8.49 (dd, J = 1.8, 1.1 Hz, 1H), 8.21-8.12 (m, 2H), 7.75 (dd, J =8.0, 1.5 Hz, 1H), 7.70-7.62 (m, 2H), 7.62-7.53 (m, 1H), 7.53-7.44 (m,1H). DMSO >98 G8 with DMF instead of THF 396 ¹H NMR (400 MHz, DMSO) δ11.71 (s, 1H), 11.10 (s, 1H), 9.42 (d, J = 1.9 Hz, 1H), 8.90-8.69 (m,2H), 8.62 (d, J = 1.7 Hz, 1H), 8.40 (dd, J = 8.8, 1.9 Hz, 1H), 8.14 (d,J = 8.7 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.84-7.69 (m, 1H), 7.57-7.40(m, 3H), 7.11-7.02 (m, 2H), 6.96 (d, J = 8.3 Hz, 1H), 3.89 (s, 3H).DMSO >98 G12 397 ¹H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 9.50 (d, J =1.6 Hz, 1H), 8.99 (d, J = 8.2 Hz, 1H), 8.88 (dd, J = 5.3, 1.5 Hz, 1H),8.30 (d, J = 2.5 Hz, 1H), 8.14-8.06 (m, 1H), 7.99-7.88 (m, 2H), 7.78-7.66 (m, 2H), 7.61-7.51 (m, 3H), 7.50-7.34 (m, 3H), 5.34 (s, 2H).DMSO >98 Method G1 398 ¹H NMR (400 MHz, DMSO) δ 9.96 (s, 1H), 9.52 (d, J= 1.4 Hz, 1H), 8.68 (dd, J = 9.9 Hz, 1H), 8.65 (d, J = 9.9 Hz, 1H), 8.16(dd, J = 2.5, 5.4 Hz, 2H), 7.68-7.41 (m, 2H), 7.78-7.66 (m, 8H),7.39-7.19 (m, 1H), 5.30 (s, 2H). DMSO >98 Method G1 399 1H NMR (DMSO-d6)pprn 12.52 (s, 1H), 9.78 (d, J = 1.56 Hz, 1H), 8.91-8.88 (m, 1H), 8.74(dd, J = 4.74, 1.60 Hz, 1H), 8.33 (brs, 1H), 8.06 (d, J = 8.56 Hz, 2H),7.93 (d, J = 9.08 hz, 1H), 7.89 (s, 1H), 7.66-7.59 (rn, 2H), 7.55 (d, J= 8.56 Hz, 2H), 4.01 (s, 3H). DMSO >98 G13 400 1H NMR (DMSO-d6) ppm12.80-12.40 (br, 1H), 9.77 (d, J = 1.84 Hz, 1H), 9.32 (d, J = 8.04 Hz,1H), 8.97 (dd, J = 5.36, 1.40 Hz, 1H), 8.34 (d, J = 2.68 Hz, 1H),8.09-8.06 (m, 3H), 7.97 (d, J = 9.12 Hz, 1H), 7.91 (s, 1H), 7.64 (dd, J= 9.12, 2.68 Hz, 1H), 7.55 (d, J = 8.60 Hz, 2H), 4.01 (s, 3H). The 1H of2HCl was not observed. DMSO >98 G13 401 1H NMR (DMSO-d6) ppm 11.14 (brs,1H), 9.58 (s, 1H), 9.13 (dd, J = 7.96 Hz, 1H), 8.93 (d, J = 5.24 Hz,1H), 8.54 (d, J = 4.72 Hz, 1H), 8.48 (d, J = 8.32 Hz, 1H), 8.28 (brs,1H), 8.09 (brt, J = 7.16 Hz, 1H), 8.02-7.96 (m, 2H), 7.65 (dd, J = 8.80,2.48 Hz, 1H), 7.34 (brt, J = 6.52 Hz, 1H), 4.01 (s, 3H). The 1H of 2HClwas not observed. DMSO >98 J2 402 1H NMR (DMSO-d6) ppm 10.89 (s, 1H),9.57 (d, J = 1.60 Hz, 1H), 9.04 (d, J = 8.04 Hz, 1H), 8.88 (dd, J =5.16, 1.40 Hz, 1H), 8.55 (dd, J = 2.64, 0.52 Hz, 1H), 8.50 (d, J = 8.92Hz, 1H), 8.22 (d, J = 2.68 Hz, 1H), 8.08 (d, J = 8.92, 2.68 Hz, 1H),7.94-7.90 (m, 2H), 7.61 (dd, J = 9.08, 2.68 Hz, 1H), 3.99 (s, 3H). The1H of 2HCl was not observed. DMSO DMSO J2 403 1H NMR (DMSO-d6) ppm 10.53(s, 1H), 9.38 (s, 1H), 8.99 (d, J = 8.08 Hz, 1H), 8.88 (d, J = 4.60 Hz,1H), 8.11 (brs, 1H), 8.01-7.95 (m, 2H), 7.90 (d, J = 8.60 Hz, 2H), 7.66(dd, J = 9.12, 2.68 Hz, 1H), 7.50 (d, J = 8.60 Hz, 2H), 6.93 (s, 1H),4.00 (s, 3H), 3.80 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 J2404 1H NMR (DMSO-d6) ppm 11.81 (brs, 1H), 9.64 (s, 1H), 9.00 (d, J =7.48 Hz, 1H), 8.85 (brs, 1H), 8.14 (d, J = 2.56 Hz, 1H), 8.00 (d, J =8.60 Hz, 2H), 7.96 (d, J = 9.08 Hz, 1H), 7.86 (br, 1H), 7.66-7.63 (m,3H), 7.25 (s, 1H), 4.00 (s, 3H). The 1H of HCl was not observed.DMSO >98 J2 405 1H NMR (DMSO-d6) ppm 11.80 (brs, 1H), 9.55 (brs, 1H),9.04 (d, J = 7.92 Hz, 1H), 8.88 (brs, 1H), 8.14 (d, J = 2.60 Hz, 1H),8.05-8.02 (m, 2H), 7.96 (d, J = 9.12 Hz, 1H), 7.89 (m, 1H), 7.64 (dd, J= 9.12, 2.60 Hz, 1H), 7.42 (t, J = 8.84 Hz, 2H), 7.23 (s, 1H), 3.99 (s,3H). The 1H of HCl was not observed. DMSO >98 J2 406 1H NMR (DMSO-d6)ppm 10.31 (s, 1H), 9.37 (s, 1H), 8.88 (m, 2H), 8.04 (d, J = 2.60 Hz,1H), 7.94 (d, J = 9.12 Hz, 1H), 7.91 (m, 1H), 7.64 (dd, J = 9.12, 2.68Hz, 1H), 7.56 (d, J = 1.83 Hz, 1H), 6.40 (d, J = 1.88 Hz, 1H), 3.98 (s,3H), 3.74 (s, 3H) . The 1H of HCl was not observed. DMSO >98 J2 407 1HNMR (DMSO-d6) ppm 12.89 (brs, 1H), 9.56 (s, 1H), 8.92 (d, J = 4.92 Hz,2H), 8.04 (d, J = 8.84 Hz, 1H), 7.98 (d, J = 2.88 Hz, 1H), 7.84 (br,1H), 7.71-7.66 (m, 3H), 7.45-7.39 (m, 2H), 4.00 (s, 3H), 3.94 (s, 3H).The 1H of 2HCl was not observed. DMSO >98 J2 408 1H NMR (DMSO-d6) ppm10.39 (s, 1H), 9.38 (s, 1H), 8.90 (d, J = 8.00 Hz, 1H), 8.84 (d, J =4.76 hz, 1H), 8.06 (d, J = 2.68 Hz, 1H), 7.95 (d, J = 9.16 Hz, 1H),7.90-7.88 (m, 3H), 7.65 (dd, J = 9.16, 2.68 Hz, 1H), 7.44 (brt, J = 7.40Hz, 2H), 7.35-7.31 (m, 1H), 6.88 (s, 1H), 3.99 (s, 3H), 3.80 (s, 3H).The 1H of HCl was not observed. DMSO >98 J2 Tempera-ture at 100° C. 4091H NMR (DMSO-d6) ppm 10.44 (brs, 1H), 9.01 (s, 1H), 8.68 (brs, 1H), 8.39(brs, 1H), 8.23 (s, 1H), 8.07 (brs, 1H), 7.84 (d, J = 9.04 Hz, 1H),7.70-7.54 (m, 2H), 7.44 (brd, J = 7.32 Hz, 2H), 7.15 (brt, J = 7.56 Hz,2H), 7.00 (brt, 7.40 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H). The 1H of HClwas not observed. DMSO >98 J2 Tempera-ture at 100° C. 410 1H NMR(DMSO-d6) ppm 11.13 (s, 1H), 9.59 (d, J = 1.64 Hz, 1H), 9.03 (brs, 1H),8.88 (brs, 1H), 8.63 (d, J = 2.52 Hz, 1H), 8.23 (d, J = 2.32 Hz, 1H),7.93-7.82 (brm, 4H), 7.61-7.53 (m, 3H), 7.35-7.31 (brm, 2H), 4.00 (s,3H). The 1H of HCl was not observed. DMSO >98 J2 Tempera-ture at 100° C.411 1H NMR (DMSO-d6) ppm 9.54 (s, 1H), 8.79 (s, 1H), 8.69 (d, J = 7.60Hz, 1H), 7.89 (brd, J = 8.96 Hz, 2H), 7.68-7.58 (m, 4H), 7.38-7.30 (m,2H), 3.98 (s, 3H). The 1H of NH— was not observed. DMSO >98 J2Tempera-ture at 100° C. 412 1H NMR (DMSO-d6) ppm 9.70 (s, 1H), 9.05 (d,J = 7.88 Hz, 1H), 8.85 (brd, J = 4.44 Hz, 1H), 8.24 (brs, 1H), 8.04 (d,J = 8.44 Hz, 2H), 7.94 (d, J = 9.00 Hz, 1H), 7.84 (m, 1H), 7.66 (d, J =8.44 Hz, 2H), 7.62 (dd, J = 9.00, 2.64 Hz, 1H), 3.99 (s, 3H). The 1H ofHCl and NH— were not observed. DMSO >98 G12 Tempera-ture at 100° C. 4131H NMR (CDCl3) ppm 15.18 (brs, 1H), 9.57 (d, J = 2.32 Hz, 1H), 8.86 (dd,J = 4.80, 1.56 Hz, 1H), 8.59-8.56 (m, 1H), 7.78-7.73 (m, 4H), 7.55-7.52(m, 1H), 7.43 (d, J = 8.56 Hz, 2H), 7.38 (dd, J = 8.88, 2.96 Hz, 1H),7.34 (s, 1H), 3.97 (s, 3H), 3.30 (s, 3H), 3.11 (s, 3H). CDCl3 >98 J2Tempera-ture at 100° C. Salt Number Starting Material 1 StartingMaterial 2 Product type 414

2 HCl 415

2 HCl 416

HCl 417

HCl 418

HCl 419

HCl 420

HCl 421

422

HCl 423

HCl 424

HCl 425

HCl 426

HCl 427

HCl 428

4 HCl 429

HCl 430

2 HCl 431

HCl 432

HCl 433

HCl 434

2 HCl 435

2 HCl 436

HCl 437

438

HCl 439

HCl 440

HCl 441

HCl 442

2 HCl 443

2 HCl 444

2 HCl 445

2 HCl 446

HCl 447

2 HCl 448

HCl 449

2 HCl 450

2 HCl 451

HCl 452

HCl 453

2 HCl 454

2 HCl 455

HCl 456

2 HCl 457

HCl 458

HCl 459

HCl 460

2 HCl 461

2 HCl 462

2 HCl 463

2 HCl 464

2 HCl 465

2 HCl 466

2 HCl 467

HCl 468

2 HCl 469

2 HCl 470

HCl 471

2 HCl 472

3 HCl 473

2 HCl 474

475

HCl 476

HCl 477

HCl 478

HCl 479

HCl 480

HCl 481

HCl 482

HCl 483

HCl 484

HCl 485

HCl 486

2 HCl 487

2 HCl 488

2 HCl 489

2 HCl 490

491

492

493

2 HCl 494

495

496

497

2 HCl 498

499

2 HCl 501

HCl 502

503

504

HCl 505

506

507

508

509

510

511

512

513

514

2 HCl 515

HCl 516

517

HCl 518

2 HCl 519

2 HCl 520

HCl 521

HCl 1758

3 HCl 1759

3 HCl ¹H NMR Purity Method Retention LCMS Number ¹H NMR Solvent percentof Coupling LCMS Time Method 414 1H NMR (DMSO-d6) ppm 9.72 (s, 1H), 9.16(brs, 1H), 8.93 (d, J = 4.36 Hz, 1H), 8.14 (br, 1H), 7.96 (brm, 2H),7.63 (dd, J = 9.08, 2.56 Hz, 1H), 7.00 (s, 1H), 3.98 (s, 3H), 2.37 (s,3H). The 1H of 2HCl and NH— were not observed. DMSO >98 G12 Temperatureat 100° C. 415 1H NMR (DMSO-d6) ppm 12.60 (brs, 1H), 9.78 (s, 1H), 9.12(d, J = 8.00 Hz, 1H), 8.86 (brs, 1H), 8.35 (brd, J = 2.60 Hz, 1H), 8.01(d, J = 8.56 Hz, 2H), 7.96 (d, J = 9.08 Hz, 1H), 7.92 (s, 1H), 7.86 (m,1H), 7.69 (d, J = 8.56 Hz, 2H), 7.63 (dd, J = 9.08, 2.60 Hz, 1H), 4.02(s, 3H). The 1H of HCl was not observed. DMSO >98 G12 Temperature at100° C. 416 1H NMR (DMSO-d6) ppm 12.80-12.40 (br, 1H), 9.79 (d, J = 1.64Hz, 1H), 9.16 (d, J = 7.88 Hz, 1H), 8.88 (d, J = 3.88 Hz, 1H), 8.36(brd, J = 2.64 Hz, 1H), 8.06-8.04 (m, 2H), 7.96 (d, J = 9.08 Hz, 1H),7.90 (m, 1H), 7.85 (s, 1H), 7.63 (dd, J = 9.08, 2.64 Hz, 1H), 7.49 (m,2H), 7.38 (m, 1H), 4.02 (s, 3H). The 1H of HCl was not observed.DMSO >98 G12 Temperature at 100° C. 417 1H NMR (DMSO-d6) ppm 12.80 (s,1H), 9.74 (d, J = 1.60 Hz, 1H), 9.01 (brs, 1H), 8.83 (brs, 1H), 8.31 (d,J = 2.64 Hz, 1H), 8.15 (d, J = 1.00 Hz, 1H), 7.96 (d, J = 9.12 Hz, 1H),7.78 (br, 1H), 7.64 (dd, J = 9.12, 2.64 Hz, 1H), 3.99 (s, 3H). The 1H ofHCl was not observed. DMSO >98 G12 Temperature at 100° C. 418 1H NMR(DMSO-d6) ppm 12.60 (br, 1H), 9.79 (d, J = 1.72 Hz, 1H), 9.19 (d, J =8.00 Hz, 1H), 8.93 (dd, J = 5.16, 1.44 Hz, 1H), 8.23 (brs, 1H), 8.10 (s,1H), 7.99 (m, 1H), 7.95 (d, J = 9.08 Hz, 1H), 7.77-7.75 (br, 2H), 7.62(dd, J = 9.08, 2.72 Hz, 1H), 7.50 (m, 2H), 7.37 (m, 1H), 3.99 (s, 3H).The 1H of HCl was not observed. DMSO >98 G12 Temperature at 100° C. 4191H NMR (DMSO-d6) ppm 12.56 (s, 1H), 9.78 (s, 1H), 9.09 (d, J = 8.20 Hz,1H), 8.84 (d, J = 3.96 Hz, 1H), 8.35 (d, J = 2.60 Hz, 1H), 8.10-8.07 (m,2H), 7.95 (d, J = 9.12 Hz, 1H), 7.83 (brt, J = 6.60 Hz, 2H), 7.63 (dd, J= 9.12, 2.60 Hz, 1H), 7.32 (m, 2H), 4.02 (s, 3H). The 1H of HCl was notobserved. DMSO >98 G12 Temperature at 100° C. 420 1H NMR (DMSO-d6) ppm9.74 (s, 1H), 9.04 (d, J = 6.68 Hz, 1H), 8.86 (brs, 1H), 8.29 (brs, 1H),8.05 (brs, J = 7.44 Hz, 2H), 7.97 (d, J = 9.08 Hz, 1H), 7.89 (br, 1H),7.67-7.58 (m, 4H), 4.00 (s, 3H). The 1H of HCl and NH— were notobserved. DMSO >98 G12 Temperature at 100° C. 421 1H NMR (DMSO-d6) ppm9.88 (s, 1H), 9.51 (dd, J = 2.16, 0.8 Hz, 1H), 8.68-8.64 (m, 2H), 7.98(d, J = 2.40 Hz, 1H), 7.91 (d, J = 8.84 Hz, 2H), 7.86 (d, J = 9.12 Hz,1H), 7.68 (d, J = 8.34 Hz, 2H), 7.58-7.53 (m, 2H), 3.98 (s, 3H).DMSO >98 G1 422 1H NMR (DMSO-d6) ppm 10.24 (br, 1H), 9.54 (s, 1H), 8.92(d, J = 7.52 Hz, 1H), 8.82 (d, J = 3.96 Hz, 1H), 8.10 (d, J = 2.44 Hz,1H), 8.03 (d, J = 8.68 Hz, 2H), 7.92 (d, J = 9.08 Hz, 1H), 7.84 (d, J =8.68 Hz, 2H), 7.81 (m, 1H), 7.77-7.75 (m, 2H), 7.62 (dd, J = 9.08, 2.44Hz, 1H), 7.50 (m, 2H), 7.38 (m, 1H), 4.01 (s, 3H). The 1H of HCl was notobserved. DMSO >98 J3 using Na₂CO₃ instead of K₂CO₃ 423 1H NMR (DMSO-d6)ppm 9.72 (s, 1H), 9.09 (d, J = 8.00 Hz, 1H), 8.89 (d, J = 4.24 Hz, 1H),8.26 (brs, 1H), 8.12-8.09 (m, 2H), 7.96 (d, J = 9.12 Hz, 1H), 7.91 (m,1H), 7.64 (dd, J = 9.12, 2.64 Hz, 1H), 7.45 (t, J = 8.80 Hz, 2H), 3.99(s, 3H). The 1H of HCl and NH— were not observed. DMSO >98 G13 usingK₂CO₃ instead of Cs₂CO₃ 424 1H NMR (DMSO-d6) ppm 10.30-10.15 (br, 1H),9.54 (s, 1H), 8.91 (brs, 1H), 8.82 (brs, 1H), 8.10 (brs, 1H), 8.04 (d, J= 8.56 Hz, 2H), 7.92 (d, J = 9.6 Hz, 1H), 7.85 (d, J = 8.56 Hz, 2H),7.80 (m, 1H), 7.79 (d, J = 8.56 Hz, 2H), 7.65-7.59 (brm, 1H), 7.55 (d, J= 8.56 Hz, 2H), 4.01 (s, 3H). The 1H of HCl was not observed. DMSO >98J3 425 1H NMR (DMSO-d6) ppm 9.91 (s, 1H), 9.53 (d, J = 1.84 Hz, 1H),8.69 (d, J = 5.56 Hz, 2H), 8.31 (t, J = 1.88 Hz, 1H), 7.99 (d, J = 2.68Hz, 1H), 7.98-7.94 (m, 1H), 7.87 (d, J = 9.08 Hz, 1H), 7.60-7.54 (m,2H), 7.46 (t, J = 8.04 Hz, 1H), 7.39-7.35 (m, 1H), 3.99 (s, 3H). The 1Hof HCl was not observed. DMSO >98 G1 426 1H NMR (DMSO-d6) ppm 10.25 (br,1H), 9.52 (s, 1H), 8.89 (brs, 1H), 8.88 (brs, 1H), 8.22 (brs, 1H), 8.11(brs, 1H), 7.98-7.92 (brm, 2H), 7.80-7.70 (brm, 3H), 7.63-7.69 (brm,2H), 7.55-7.50 (brm, 3H), 7.41 (m, 1H), 4.00 (s, 3H). The 1H of HCl wasnot observed. DMSO >98 G13 using K₂CO₃ instead of Cs₂CO₃ at 120° C. 4271H NMR (DMSO-d6) ppm 10.31 (br, 1H), 9.51 (brs, 1H), 8.92 (brd, J = 7.44Hz, 1H), 8.84 (brs, 1H), 8.22 (brs, 1H), 8.12 (brd, J = 2.28 Hz, 1H),8.00-7.93 (brm, 2H), 7.83-7.77 (brm, 3H), 7.64-7.54 (brm, 5H), 4.01 (s,3H). The 1H of HCl was not observed. DMSO >98 J3 using Na₂CO₃ instead ofK₂CO₃ 428 1H NMR (DMSO-d6) ppm 9.73 (d, J = 1.72 Hz, 1H), 9.06 (d, J =8.08 Hz, 1H), 8.88 (d, J = 3.72 Hz, 1H), 8.28 (brs, 1H), 8.01-7.96 (m,3H), 7.88 (m, 1H), 7.81 (d, J = 8.60 Hz, 2H), 7.65 (dd, J = 9.08, 2.64Hz, 1H), 4.00 (s, 3H). The 1H of 4HCl and NH— were not observed.DMSO >98 G13 using K₂CO₃ instead of Cs₂CO₃ 429 1H NMR (DMSO-d6) ppm12.60 (br, 1H), 9.78 (d, J = 1.76 Hz, 1H), 9.28 (d, J = 8.04 Hz, 1H),8.95 (dd, J = 5.20, 1.20 Hz, 1H), 8.36 (d, J = 2.28 Hz, 1H), 8.04-7.93(m, 4H), 7.77 (s, 1H), 7.64 (dd, J = 9.12, 2.68 Hz, 1H), 7.30 (d, J =8.04 Hz, 2H), 4.02 (s, 3H), 2.36 (s, 3H). The 1H of HCl was notobserved. DMSO >98 G13 using K₂CO₃ instead of Cs₂CO₃ 430 1H NMR(DMSO-d6) ppm 12.70-12.40 (br, 1H), 9.71 (s, 1H), 9.27 (d, J = 8.20 Hz,1H), 8.94 (d, J = 4.24 Hz, 1H), 8.34 (d, J = 2.64 Hz, 1H), 8.13 (t, J =1.80 Hz, 1H), 8.04-7.95 (m, 4H), 7.63 (dd, J = 9.08, 2.68 Hz, 1H), 7.52(t, J = 7.88 Hz, 1H), 7.44-7.42 (m, 1H), 4.02 (s, 3H). The 1H of 2HClwas not observed. DMSO >98 G13 using K₂CO₃ instead of Cs₂CO₃ 431 1H NMR(DMSO-d6) ppm 12.57 (br, 1H), 9.80 (brs, 1H), 9.04 (d, J = 7.36 Hz, 1H),8.82 (brs, 1H), 8.34 (brs, 1H), 7.99 (brd, J = 7.28 Hz, 1H), 7.95 (d, J= 9.08 Hz, 1H), 7.82 (brs, 1H), 7.76 (brm, 1H), 7.62 (m, 2H), 7.50-7.41(m, 2H), 4.00 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13using K₂CO₃ instead of Cs₂CO₃ 432 1H NMR (DMSO-d6) ppm 10.40 (br, 1H),9.23 (s, 1H), 8.80 (d, J = 4.68 Hz, 1H), 8.66 (brd, J = 8.20 Hz, 1H),7.92 (brs, 1H), 7.87 (brd, J = 9.28 Hz, 1H), 7.78 (brm, 1H), 7.63-7.52(m, 5H), 7.47-7.44 (m, 2H), 7.21-7.12 (m, 3H), 3.91 (s, 3H). The 1H ofHCl was not observed. DMSO >98 G13 using K₂CO₃ instead of Cs₂CO₃ 433 1HNMR (DMSO-d6) ppm 12.34 (br, 1H), 9.75 (s, 1H), 9.01 (d, J = 7.52 Hz,1H), 8.81 (brs, 1H), 8.40-8.20 (br, 1H), 7.92 (d, J = 9.08 Hz, 1H), 7.77(m, 1H), 7.60 (dd, J = 9.08, 2.72 Hz, 1H), 6.95 (br, 1H), 3.98 (s, 3H),2.67 (m, 1H), 2.05 (m, 2H), 1.83-1.70 (m, 3H), 1.54-1.23 (m, 5H). The 1Hof HCl was not observed. DMSO >98 G13 using K₂CO₃ instead of Cs₂CO₃ 4341H NMR (DMSO-d6) ppm 12.58 (br, 1H), 9.79 (s, 1H), 9.19 (d, J = 7.32 Hz,1H), 8.90 (d, J = 5.6 Hz, 1H), 8.36 (s, 1H), 7.96 (d, J = 9.08 Hz, 1H),7.94 (m, 1H), 7.88 (s, 1H), 7.65-7.62 (m, 3H), 7.40 (t, J = 8.16 Hz,1H), 6.96-6.93 (m, 1H), 4.02 (s, 3H), 3,84 (s, 3H). The 1H of 2HCl wasnot observed. DMSO >98 G13 using K₂CO₃ instead of Cs₂CO₃ 435 1H NMR(DMSO-d6) ppm 12.80-12.40 (br, 1H), 9.79 (d, J = 1.44 Hz, 1H), 9.26 (d,J = 8.24 Hz, 1H), 8.93 (d, J = 4.08 Hz, 1H), 8.36 (d, J = 2.28 Hz, 1H),8.02-7.96 (m, 4H), 7.68 (s, 1H), 7.64 (dd, J = 9.12, 2.68 Hz, 1H), 7.05(d, J = 8.92 Hz, 2H), 4.02 (s, 3H), 3.82 (s, 3H). The 1H of 2HCl was notobserved. DMSO >98 G13 using K₂CO₃ instead of Cs₂CO₃ 436 1H NMR(DMSO-d6) ppm 12.52 (br, 1H), 9.79 (s, 1H), 9.23 (d, J = 8.00 Hz, 1H),8.91 (d, J = 4.12 Hz, 1H), 8.35 (brs, 1H), 8.25 (d, J = 7.6 Hz, 1H),7.96 (d, J = 9.08 Hz, 1H), 7.93 (m, 1H), 7.85 (s, 1H), 7.64 (dd, J =9.08, 2.68 Hz, 1H), 7.39-7.35 (m, 1H), 7.18 (d, J = 7.72 Hz, 1H),7.11-7.07 (m, 1H), 4.02 (s, 3H), 3.96 (s, 3H). The 1H of HCl was notobserved. DMSO >98 G13 using K₂CO₃ instead of Cs₂CO₃ 437 1H NMR(DMSO-d6) ppm 9.94 (s, 1H), 9.27 (d, J = 1.92 Hz, 1H), 8.59 (dd, J =4.72, 1.68 Hz, 1H), 8.45 (dt, J = 8.04, 1.8 Hz, 1H), 7.96 (d, J = 2.72Hz, 1H), 7.84 (d, J = 8.28 Hz, 2H), 7.67 (d, J = 8.00 Hz, 1H), 7.55 (m,2H), 7.46-7.43 (m, 1H), 7.33 (m, 1H), 3.96 (s, 3H). DMSO >98 G13 usingK₂CO₃ instead of Cs₂CO₃ at 120° C. 438 1H NMR (DMSO-d6) ppm 10.48 (br,1H), 9.23 (s, 1H), 8.83 (brd, J = 3.68 Hz, 1H), 8.70 (brd, J = 7.36 Hz,1H), 7.95 (brs, 1H), 7.91 (d, J = 9.12 Hz, 1H), 7.82 (m, 1H), 7.63-7.51(m, 5H), 7.48 (d, J = 8.52 Hz, 2H), 7.26 (d, J = 8.52 Hz, 2H), 3.93 (s,3H). The 1H of HCl was not observed. DMSO >98 J3 using Na₂CO₃ instead ofK₂CO₃ 439 1H NMR (DMSO-d6) ppm 12.60 (br, 1H), 9.78 (s, 1H), 9.17 (d, J= 7.96 Hz, 1H), 8.88 (d, J = 4.20 Hz, 1H), 8.35 (d, J = 2.60 Hz, 1H),8.24-8.21 (m, 1H), 7.96 (d, J = 9.08 Hz, 1H), 7.91-7.88 (brm, 1H), 7.74(d, J = 2.48 Hz, 1H), 7.63 (dd, J = 9.08, 2.60 Hz, 1H), 7.47-7.41 (m,1H), 7.36 8m, 2H), 4.02 (s, 3H). The 1H of HCl was not observed.DMSO >98 G13 at 100° C. 440 1H NMR (DMSO-d6) ppm 12.60-12.45 (br, 1H),9.79 (d, J = 1.52 Hz, 1H), 9.15 (d, J = 8.36 Hz, 1H), 8.88 (d, J = 5.04Hz, 1H), 8.35 (d, J = 2.44 Hz, 1H), 7.96 (d, J = 9.12 Hz, 1H), 7.89(brt, J = 7.08 Hz, 2H), 7.82 (brm, 1H), 7.81 (s, 1H), 7.63 (dd, J =9.12, 2.44 Hz, 1H), 7.37 (t, J = 7.64 Hz, 1H), 7.19 (d, J = 7.48 Hz,1H), 4.02 (s, 3H), 2.40 (s, 3H). The 1H of HCl was not observed.DMSO >98 G13 at 100° C. 441 1H NMR (DMSO-d6) ppm 12.60 (br, 1H), 9.77(s, 1H), 9.25 (d, J = 8.08 Hz, 1H), 8.93 (d, J = 4.28 Hz, 1H), 8.34 (d,J = 2.60 Hz, 1H), 8.01-7.84 (m, 5H), 7.63 (dd, J = 9.12, 2.60 Hz, 1H),7.56-7.51 (m, 1H), 7.21 (m, 1H). The 1H of HCl was not observed.DMSO >98 G13 at 100° C. 442 1H NMR (DMSO-d6) ppm 12.66 (brs, 1H), 9.78(d, J = 1.68 Hz, 1H), 9.27 (d, J = 8.08 Hz, 1H), 8.94 (dd, J = 5.20,1.40 Hz, 1H), 8.36 (d, J = 2.56 Hz, 1H), 8.17 (d, J = 8.84 Hz, 2H), 8.01(m, 1H), 7.97 (d, J = 9.08 Hz, 1H), 7.93 (s, 1H), 7.64 (dd, J = 9.08,2.56 Hz, 1H), 7.49 (brd, J = 8.84 Hz, 2H), 4.02 (s, 3H). The 1H of 2HClwas not observed. DMSO >98 G13 at 100° C. 443 1H NMR (DMSO-d6) ppm 12.64(br, 1H), 9.79 (s, 1H), 9.13 (d, J = 7.56 Hz, 1H), 8.87 (d, J = 5.08 Hz,1H), 8.36 (d, J = 2.60 Hz, 1H), 8.27 (d, J = 8.00 Hz, 2H), 8.08 (s, 1H),7.96 (d, J = 9.12 Hz, 1H), 7.87 (m, 1H), 7.86 (d, J = 8.00 Hz, 2H), 7.64(dd, J = 9.12, 2.60 Hz, 1H), 4.02 (s, 3H). The 1H of 2HCl was notobserved. DMSO >98 G13 at 100° C. 444 1H NMR (MeOD-d4) ppm 9.79 (s, 1H),9.37 (br, 1H), 8.49 (dd, J = 5.28, 1.32 Hz, 1H), 8.12 (m, 1H), 8.09 (d,J = 2.72 Hz, 1H), 7,98 (d, J = 9.16 Hz, 1H), 7.68 (dd, J = 9.16, 2.72Hz, 1H), 7.58 (d, J = 7.12 Hz, 1H), 7.42-7.30 (m, 3H), 7.30 (s, 1H),4.05 (s, 3H), 2.50 (s, 3H). The 1H of 2HCl was not observed. MeOD >98G13 445 1H NMR (DMSO-d6) ppm 12.59 (br, 1H), 9.78 (d, J = 1.48 Hz, 1H),9,19 (d, J = 8.00 Hz, 1H), 8.90 (dd, J = 5.16, 1.48 Hz, 1H), 8.34 (d, J= 2.60 Hz, 1H), 8.10-8.04 (m, 1H), 7.97-7.88 (m, 4H), 7.64 (dd, J = 2.60Hz, 1H), 7.59-7.52 (m, 1H), 4.02 (s, 3H). The 1H of 2HCl was notobserved. DMSO >98 G13 446 1H NMR (DMSO-d6) ppm 12.61 (br, 1H), 9.78 (d,J = 1.72 Hz, 1H), 9.20 (d, J = 7.92 Hz, 1H), 8.90 (d, J = 4.00 Hz, 1H),8.35 (d, J = 2.60 Hz, 1H), 8.27-8.21 (m, 1H), 7.96 (d, J = 9.12 Hz, 1H),7.93 (m, 1H), 7.71 (d, J = 2.56 Hz, 1H), 7.64 (dd, J = 9.12, 2.60 Hz,1H), 7.43 (m, 1H), 7.27 (m, 1H), 4.02 (s, 1H). The 1H of HCl was notobserved. DMSO >98 G13 447 1H NMR (DMSO-d6) ppm 12.57 (br, 1H), 9.77 (d,J = 1.76 Hz, 1H), 9.25 (d, J = 8.08 Hz, 1H), 8.93 (dd, J = 5.16, 1.2 Hz,1H), 8.34 (d, J = 2.60 Hz, 1H), 8.29 (t, J = 1.76 Hz, 1H), 8.05 (dd, J =7.84, 1.12 Hz, 1H), 8.02-7.98 (m, 1H), 7.99 (s, 1H), 7.96 (d, J = 9.08Hz, 1H), 7.64 (dd, J = 9.08, 2.60 Hz, 1H), 7.58-7.56 (m, 1H), 7.45 (t, J= 7.84 Hz, 1H), 4.02 (s, 3H). The 1H of 2HCl was not observed. DMSO >98G13 448 1H NMR (DMSO-d6) ppm 12.62 (br, 1H), 9.77 (d, J = 1.52 Hz, 1H),9.10 (d, J = 8.16 Hz, 1H), 8.85 (dd, J = 5.00, 1.56 Hz, 1H), 8.34 (d, J= 2.60 Hz, 1H), 8.24 (d, J = 8.60 Hz, 2H), 8.13 (s, 1H), 7.96 (d, J =8.60 Hz, 2H), 7.96 (d, J = 9.08 Hz, 1H), 7.86-7.83 (brm, 1H), 7.63 (dd,J = 9.08, 2.60 Hz, 1H), 4.02 (s, 3H). The 1H of HCl was not observed.DMSO >98 G13 449 1H NMR (DMSO-d6) ppm 12.56 (brs, 1H), 9.79 (brs, 1H),9.11 (d, J = 8.04 Hz, 1H), 8.87 (brs, 1H), 8.43 (brs, 1H), 8.34 (brs,2H), 8.09 (s, 1H), 7.96 (d, J = 9.08 Hz, 1H), 7.87 (brs, 1H), 7.74 (brd,J = 5.00 Hz, 2H), 7.64 (dd, J = 9.08, 2.48 Hz, 1H), 4.03 (s, 3H). The 1Hof 2HCl was not observed. DMSO >98 G13 at 100° C. 450 1H NMR (DMSO-d6)ppm 12.63 (br, 1H), 9.80 (d, J = 1.72 Hz, 1H), 9.27 (d, J = 8.16 Hz,1H), 8.93 (dd, J = 5.20, 1.36 Hz, 1H), 8.33 (d, J = 2.24 Hz, 1H), 7.99(m, 1H), 7.98 (d, J = 9.08 Hz, 1H), 7.88 (brd, J = 7.72 Hz, 1H),7.71-7.75 (m, 2H), 7.70-7.63 (m, 2H), 7.45 (s, 1H), 3.98 (s, 3H). The 1Hof 2HCl was not observed. DMSO >98 G13 at 100° C. 451 1H NMR (DMSO-d6)ppm 12.70 (br, 1H), 9.79 (d, J = 1.60 Hz, 1H), 9.30 (d, J = 7.56 Hz,1H), 8.95 (d, J = 4.96 Hz, 1H), 8.34 (d, J = 2.20 Hz, 1H), 8.02 (m, 1H),7.98 (d, J = 9.12 Hz, 1H), 7.85-7.77 (m, 2H), 7.73 (s, 1H), 7.64 (dd, J= 9.12, 2.68 Hz, 1H), 7.52 (m, 1H), 7.36 (m, 1H), 4.00 (s, 3H). The 1Hof HCl was not observed. DMSO >98 G13 452 1H NMR (DMSO-d6) ppm 12.64(br, 1H), 9.78 (d, J = 1.72 Hz, 1H), 9.19 (d, J = 7.92 Hz, 1H), 8.90 (d,J = 3.88 Hz, 1H), 8.36 (d, J = 2.64 Hz, 1H), 8.02-7.91 (m, 3H), 7.83 (d,J = 2.40 hz, 1H), 7.64 (dd, J = 9.08, 2.64 Hz, 1H), 7.46 (m, 1H), 7.36(m, 1H), 4.02 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13 4531H NMR (DMSO-d6) ppm 12.62 (br, 1H), 9.77 (d, J = 1.84 Hz, 1H), 9.30 (d,J = 8.00 Hz, 1H), 8.46 (dd, J = 5.36, 1.48 Hz, 1H), 8.48 (br, 1H),8.39-8.33 (m, 2H), 8.08 (s, 1H), 8.05 (m, 1H), 7.97 (d, J = 9.12 Hz,1H), 7.85-7.83 (m, 1H), 7.71 (t, J = 7.84 Hz, 1H), 7.64 (dd, J = 9.12,2.60 Hz, 1H), 4.02 (s, 3H). The 1H of 2HCl was not observed. DMSO >98G13 454 1H NMR (DMSO-d6) ppm 12.65 (br, 1H), 9.79 (d, J = 1.72 Hz, 1H),9.25 (d, J = 8.04 Hz, 1H), 8.92 (d, J = 5.36 Hz, 1H), 8.36 (d, J = 2.60Hz, 1H), 8.24-8.22 (,m, 1H), 7.97 (d, J = 9.08 Hz, 1H), 7.96 (m, 1H),7.69 (s, 1H), 7.65 (dd, J = 9.08, 2.60 Hz, 1H), 7.55 (m, 3H), 4.02 (s,3H). The 1H of 2HCl was not observed. DMSO >98 G13 455 1H NMR (DMSO-d6)ppm 12.52 (br, 1H), 9.78 (d, J = 1.48 Hz, 1H), 9.03 (d, J = 6.6 Hz, 1H),8.81 (d, J = 4.72 Hz, 1H), 8.34 (d, J = 2.56 Hz, 1H), 8.09 (d, J = 7.88Hz, 1H), 8.03 (brs, 2H), 7.96 (d, J = 9.12 Hz, 1H), 7.78 (br, 1H), 7.65(m, 2H), 7.38 (m, 1H), 4.02 (s, 3H). The 1H of HCl was not observed.DMSO >98 G13 456 1H NMR (DMSO-d6) ppm 12.45 (br, 1H), 9.78 (d, J = 1.64Hz, 1H), 9.15 (br, 1H), 8.89 (d, J = 4.52 Hz, 1H), 8.30 (brs, 1H), 7.94(d, J = 9.08 Hz, 1H), 7.90 (brm, 1H), 7.76 (m, 2H), 7.62 (dd, J = 9.08,2.64 Hz, 1H), 7.51 (m, 2H), 7.40 (m, 1H), 3.99 (s, 3H), 2.61 (s, 3H).The 1H of 2HCl was not observed. DMSO >98 G13 457 1H NMR (DMSO-d6) ppm12.55 (br, 1H), 9.78 (d, J = 1.48 Hz, 1H), 9.08 (d, J = 8.48 Hz, 1H),8.84 (dd, J = 5.04, 1.56 Hz, 1H), 8.34 (d, J = 2.72 Hz, 1H), 8.09 (s,1H), 7.96 (d, J = 9.12 Hz, 1H), 7.84 (m, 1H), 7.77 (m, 2H), 7.64 (dd, J= 9.12, 2.72 Hz, 1H), 7.25 (m, 1H), 4.02 (s, 3H). The 1H of HCl was notobserved. DMSO >98 G13 458 1H NMR (DMSO-d6) ppm 12.55 (br, 1H), 9.77 (d,J = 1.56 Hz, 1H), 9.14 (d, J = 8.00 Hz, 1H), 8.87 (dd, J = 5.08, 1.48Hz, 1H), 8.34 (d, J = 2.60 Hz, 1H), 7.98 (m, 1H), 7.96 (d, J = 9.08 Hz,1H), 7.89-7.86 (brm, 1H), 7.83 (d, J = 2.44 Hz, 1H), 7.64 (dd, J = 9.08,2.60 Hz, 1H), 7.47-7.41 (m, 1H), 7.29 (m, 1H), 4.02 (s, 3H). The 1H ofHCl was not observed. DMSO >98 G13 459 1H NMR (DMSO-d6) ppm 12.66 (br,1H), 9.79 (d, J = 1.60 Hz, 1H), 9.25 (d, J = 7.16 Hz, 1H), 8.92 (d, J =5.20 Hz, 1H), 8.35 (d, J = 2.56 Hz, 1H), 7.98 (d, J = 9.12 Hz, 1H), 7.97(m, 1H), 7.68 (s, 1H), 7.64 (dd, J = 9.12, 2.56 Hz, 1H), 7.55 (m, 1H),7.27 (m, 2H), 3.99 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13460 1H NMR (DMSO-d6) ppm 9.73 (s, 1H), 9.17 (brs, 1H), 8.92 (dd, J =5.16, 1.4 Hz, 1H), 8.30-8.10 (br, 1H), 7.97 (d, J = 9.04 Hz, 1H), 7.96(m, 1H), 7.63 (dd, J = 9.04, 2.72 Hz, 1H), 7.02 (s, 1H), 3.98 (s, 3H),2.57 (d, J = 7.16 Hz, 2H), 2.08 (m, 1H), 0.94 (d, J = 6.60 Hz, 6H). The1H of HCl and NH— were not observed. DMSO >98 G13 461 1H NMR (DMSO-d6)ppm 12.80-12.20 (br, 1H), 9.78 (d, J = 1.76 Hz, 1H), 9.28 (d, J = 8.04Hz, 1H), 8.96 (dd, J = 5.28, 1.32 Hz, 1H), 8.29 (brs, 1H), 8.07-8.03(brm, 1H), 7.95 (d, J = 9.12 Hz, 1H), 7.79 (d, J = 8.60 Hz, 2H), 7.62(dd, J = 9.12, 2.64 Hz, 1H), 7.57 (d, J = 8.60 Hz, 2H), 3.99 (s, 3H),2.61 (brs, 3H). The 1H of 2HCl was not observed. DMSO >98 G13 462 1H NMR(DMSO-d6) ppm 12.80-12.20 (br, 1H), 9.74 (s, 1H), 9.19 (d, J = 4.96 Hz,1H), 8.91 (dd, J = 5.2, 1.4 Hz, 1H), 8.22 (brs, 1H), 7.96 (br, 1H), 7.95(d, J = 9.08 Hz, 1H), 7.61 (dd, J = 9.08, 2.68 Hz, 1H), 7.35-7.31 (m,4H), 7.23 (m, 1H), 7.09 (brs, 1H), 4.07 (brs, 2H), 3.96 (brs, 3H). The1H of 2HCl was not observed. DMSO >98 G13 463 1H NMR (DMSO-d6) ppm 12.50(br, 1H), 9.78 (d, J = 1.76 Hz, 1H), 9.25 (brs, 1H), 8.96 (brd, J = 4.68Hz, 1H), 8.29 (brs, 1H), 8.04 (brs, 1H), 7.96 (d, J = 9.20 Hz, 1H), 7.70(brm, 2H), 7.63 (dd, J = 9.20, 2.68 Hz, 1H), 7.51 (brm, 2H), 7.41 (brm,1H), 3.99 (s, 3H), 3.02 (q, J = 7.40 Hz, 2H), 1.49 (t, J = 7.40 Hz, 3H).The 1H of 2HCl was not observed. DMSO >98 G13 464 1H NMR (DMSO-d6) ppm12.53 (br, 1H), 9.78 (d, J = 1.76 Hz, 1H), 9.20 (d, J = 8.36 Hz, 1H),8.94 (dd, J = 5.2, 1.4 Hz., 1H), 8.29 (brs, 1H), 8.00 (brm, 1H), 7.96(d, J = 9.12 Hz, 1H), 7.66-7.61 (m, 3H), 7.52 (brm, 2H), 7.43 (t, J =7.40 Hz, 1H), 3.98 (s, 3H), 1.43 (d, J = 6.8 Hz, 6H). The 1H of 2HCl wasnot observed. The CH proton of iPr group was not observed because ofoverlapping the H2O peak. DMSO >98 G13 465 1H NMR (DMSO-d6) ppm 12.59(brs, 1H), 9.77 (d, J = 1.72 Hz, 1H), 9.25 (d, J = 7.76 Hz, 1H), 8.96(d, J = 4.04 Hz, 1H), 8.29 (br, 1H), 8.04 (m, 1H), 7.96 (d, J = 9.12 Hz,1H), 7.69 (brd, J = 7.12 Hz, 2H), 7.63 (dd, J = 9.12, 2.68 Hz, 1H), 7.51(t, J = 7.36 Hz, 2H), 7.42 (t, J = 7.36 Hz, 1H), 3.99 (s, 3H), 2.96 (t,J = 7.52 Hz, 2H), 1.78 (m, 2H), 1.01 (t, J = 7.24 Hz, 3H). The 1H of2HCl was not observed. DMSO >98 G13 466 1H NMR (DMSO-d6) ppm 12.96 (brs,1H), 9.74 (d, J = 2.04 Hz, 1H), 9.11 (d, J = 7.96 Hz, 1H), 8.90 (d, J =4.96 Hz, 1H), 8.31 (brd, J = 2.64 Hz, 1H), 7.97 (d, J = 9.12 Hz, 1H),7.87 (brm, 1H), 7.83-7.80 (m, 2H), 7.64 (dd, J = 9.12, 2.62 Hz, 1H),7.48 (m, 3H), 4.25 (q, J = 7.04 Ha, 2H), 3.98 (s, 3H), 1.29 (t, J = 7.04Hz, 3H). The 1H of 2HCl was not observed. DMSO >98 G13 467 1H NMR(DMSO-d6) ppm 12.63 (br, 1H), 9.76 (d, J = 1.76 Hz, 1H), 9.29 (d, J =8.16 Hz, 1H), 8.95 (dd, J = 5.28, 1.36 Hz, 1H), 8.32 (brd, J = 2.60 Hz,1H), 8.07 (d, J = 8.52 Hz, 2H), 8.08-8.00 (m, 1H), 7.95 (d, J = 9.12 Hz,1H), 7.90 (s, 1H), 7.61 (dd, J = 9.12, 2.60 Hz, 1H), 7.55 (d, J = 8.52Hz, 2H), 4.24 (q, J = 6.88 Hz, 2H), 1.47 (t, J = 6.88 Hz, 3H). The 1H ofHCl was not observed. DMSO >98 G13 468 1H NMR (DMSO-d6) ppm 12.58 (brs,1H), 9.76 (d, J = 1.80 Hz, 1H), 9.27 (d, J = 8.16 Hz, 1H), 8.94 (dd, J =5.20, 1.32 Hz, 1H), 8.32 (d, J = 2.48 Hz, 1H), 8.09-8.01 (m, 2H),7.96-7.89 (m, 3H), 7.62-7.52 (m, 2H), 4.29 (q, J = 6.88 Hz, 2H), 1.47(t, J = 6.88 Hz, 3H). The 1H of 2HCl was not observed. DMSO >98 G13 4691H NMR (DMSO-d6) ppm 9.72 (s, 1H), 9.13 (brd, J = 5.52 Hz, 1H), 8.92 (d,J = 3.52 Hz, 1H), 8.16 (brs, 1H), 7.95 (brd, J = 9.08 Hz, 2H), 7.62 (dd,J = 2.4 Hz, 1H), 7.39 (brs, 1H), 3.97 (s, 3H), 2.47 (s, 3H). The 1H of2HCl and NH— were not observed. DMSO >98 G13 470 1H NMR (DMSO-d6) ppm12.58 (brs, 1H), 9.76 (d, J = 1.68 Hz, 1H), 9.17 (d, J = 8.12 Hz, 1H),8.89 (dd, J = 5.12, 1.48 Hz, 1H), 8.32 (d, J = 2.56 Hz, 1H), 8.01-8.00(m, 1H), 7.94 (d, J = 9.08 Hz, 1H), 7.930-7.90 (m, 1H), 7.81 (d, J = 2.4Hz, 1H), 7.60 (dd, J = 9.08, 2.40 Hz, 1H), 7.50-7.43 (m, 1H), 7.38-7.33(m, 1H), 4.28 (q, J = 7.00 Hz, 2H), 1.47 (t, J = 7.00 Hz, 3H). The 1H ofHCl was not observed. DMSO >98 G13 471 1H NMR (DMSO-d6) ppm 12.53 (brs,1H), 9.73 (d, J = 1.76 Hz, 1H), 9.29 (d, J = 8.16 Hz, 1H), 8.95 (dd, J =5.32, 1.36 Hz, 1H), 8.29 (d, J = 2.56 Hz, 1H), 8.05-8.02 (brm, 1H),7.97-7.92 (m, 1H), 7.93 (d, J = 9.08 Hz, 1H), 7.78 (d, J = 2.36 Hz, 1H),7.60 (dd, J = 9.08, 2.6 Hz, 1H), 7.46-7.40 (m, 1H), 7.31-7.25 (m, 1H),4.27 (q, J = 6.92 Hz, 2H), 1.47 (t, J = 6.92 Hz, 3H). The 1H of 2HCl wasnot observed. DMSO >98 G13 472 1H NMR (DMSO-d6) ppm 12.61 (brs, 1H),9.76 (d, J = 1.8 Hz, 1H), 9.29 (d, J = 8.16 Hz, 1H), 8.95 (dd, J = 5.24,1.2 Hz, 1H), 8.32 (d, J = 2.52 Hz, 1H), 8.24-8.20 (m, 1H), 8.05-8.01(brm, 1H), 7.95 (d, J = 9.08 Hz, 1H), 7.68 (d, J = 2.52 HZ, 1H), 7.61(dd, J = 9.08, 2.52 Hz, 1H), 7.46-7.40 (m, 1H), 7.28-7.24 (m, 1H), 4.28(q, J = 6.92 Hz, 2H), 1.47 (t, J = 6.92 Hz, 3H). The 1H of 3HCl was notobserved. DMSO >98 G13 473 1H NMR (DMSO-d6) ppm 12.63 (brs, 1H), 9.78(d, J = 1.68 Hz, 1H), 9.32 (d, J = 8.12 Hz, 1H), 8.97 (d, J = 5.24 Hz,1H), 8.35 (d, J = 2.16 Hz, 1H), 8.08-8.04 (m, 3H), 7.96 (d, J = 9.08 Hz,1H), 7.85 (s, 1H), 7.62 (dd, J = 9.08, 2.52 Hz, 1H), 7.49 (t, J = 7.44Hz, 2H), 7.38 (t, J = 7.28 Hz, 1H), 4.30 (q, J = 6.96 Hz, 2H), 1.47 (t,J = J = 6.96 Hz, 3H). The 1H of 2HCl was not observed. DMSO >98 G13 4741H NMR (DMSO-d6) ppm 12.68 (s, 1H), 9.73 (d, J = 1.64 Hz, 1H), 8.87-8.84(m, 1H), 8.75-8.73 (m, 1H), 8.33 (brs, 1H), 8.24 (brs, 1H). 7.93 (d, J =9.16 Hz, 1H), 7.64-7.59 (m, 2H), 4.34 (q, J = 7.08 Hz, 2H), 3.98 (s,3H), 1.34 (t, J = 7.08 Hz, 3H). DMSO >98 G13 475 1H NMR (300 MHz, DMSO)δ 10.35 (s, 1H), 9.42 (s, 1H), 8.99-8.76 (m, 2H), 8.11 (d, J = 6.7 Hz,1H), 7.99-7.75 (m, 3H), 7.67-7.43 (m, 2H), 7.23 (d, J = 8.2 Hz, 1H),4.14 (s, 3H). DMSO 98 G1 381   (M + 1) 2.07 Method A (Formic acid) 4761H NMR (300 MHz, DMSO) δ 13.78 (s, 1H), 9.62 (d, J = 1.7 Hz, 1H), 9.21(d, J = 8.1 Hz, 1H), 8.98 (d, J = 4.2 Hz, 1H), 8.07 (dd, J = 7.9, 5.3Hz, 1H), 7.83 (d, J = 9.1 Hz, 2H), 7.63-7.50 (m, 4H), 7.41 (d, J = 6.5Hz, 2H), 7.14 (d, J = 2.5 Hz, 1H), 5.30 (s, 1H), 3.91 (s, 3H), 2.15 (s,3H). DMSO 95 Method G1 468.1 (M + 1) Method C 477 1H NMR (300 MHz, DMSO)δ 13.78 (s, 1H), 9.64 (d, J = 1.5 Hz, 1H), 9.11 (d, J = 8.2 Hz, 1H),8.90 (d, J = 3.8 Hz, 1H), 7.95 (dd, J = 10.6, 2.6 Hz, 1H), 7.84 (d, J =9.1 Hz, 2H), 7.60-7.48 (m, 4H), 7.38 (d, J = 6.5 Hz, 2H), 7.17 (d, J =2.4 Hz, 1H), 5.28 (s, 1H), 4.14 (q, J = 6.9 Hz, 2H), 2.15 (s, 3H), 1.42(t, J = 6.9 Hz, 3H). DMSO 95 Method G1 482.1 (M + 1) Method C 478 1H NMR(300 MHz, DMSO) δ 12.59 (s, 1H), 9.56 (s, 1H), 8.70 (d, J = 5.8 Hz, 2H),8.58 (d, J = 5.2 Hz, 1H), 7.95 (d, J = 5.2 Hz, 2H), 7.87 (d, J = 9.1 Hz,2H), 7.64-7.49 (m, 2H), 7.40 (d, J = 2.4 Hz, 1H), 4.21 (q, J = 6.8 Hz,2H), 1.44 (t, J = 6.9 Hz, 3H). DMSO 99 Method G1 392.1 (M + 1) Method C479 1H NMR (300 MHz, DMSO) δ 13.75 (s, 1H), 9.60 (s, 1H), 8.98 (s, 1H),8.82 (d, J = 3.6 Hz, 1H), 7.82 (d, J = 9.0 Hz, 3H), 7.52 (d, J = 9.3 Hz,1H), 7.15 (s, 1H), 6.94-6.62 (s, 1H), 4.13 (d, J = 6.9 Hz, 2H), 2.90 (d,J = 21.9 Hz, 4H), 2.41 (s, 2H), 1.43 (t, J = 6.9 Hz, 3H). DMSO 95 MethodG1 432.1 (M + 1) Method C 480 1H NMR (300 MHz, DMSO) δ 12.50 (s, 1H),9.56 (s, 1H), 8.89 (s, 1H), 8.68 (d, J = 5.3 Hz, 2H), 8.00-7.79 (m, 3H),7.73 (d, J = 7.2 Hz, 4H), 7.62-7.38 (m, 9H), 7.34 (d, J = 2.2 Hz, 2H),4.18 (dd, J = 13.5, 6.5 Hz, 2H), 1.43 (t, J = 6.9 Hz, 3H). DMSO 99Method G1 468.1 (M + 1) Method C 481 1H NMR (300 MHz, DMSO) δ 12.51 (s,1H), 9.54 (s, 1H), 8.86 (s, 1H), 8.74-8.61 (m, 2H), 7.90 (s, J = 15.7Hz, 2H), 7.83 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 7.1 Hz, 2H), 7.63-7.40(m, 6H), 7.33 (d, J = 2.3 Hz, 1H), 3.92 (s, 3H). DMSO 99 Method G1 454.1(M + 1) Method C 482 1H NMR (300 MHz, DMSO) δ 13.70 (s, 1H), 9.70 (d, J= 2.1 Hz, 1H), 8.81 (d, J = 8.0 Hz, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H),7.90 (d, J = 9.1 Hz, 1H), 7.66-7.53 (m, 2H), 7.29 (d, J = 2.2 Hz, 1H),3.95 (s, 3H), 2.78 (d, J = 12.9 Hz, 4H), 1.78 (s, 4H). DMSO 99 Method G1432.1 (M + 1) Method C 483 1H NMR (300 MHz, DMSO) δ 13.64 (s, 1H), 9.68(s, 1H), 8.79 (d, J = 7.9 Hz, 1H), 8.69 (d, J = 4.7 Hz, 1H), 7.86 (d, J= 9.0 Hz, 1H), 7.63-7.50 (m, 2H), 7.24 (s, 1H), 4.18 (q, J = 6.7 Hz,2H), 2.76 (d, J = 10.4 Hz, 4H), 1.78 (s, 4H), 1.43 (t, J = 6.9 Hz, 3H).DMSO 99 Method G1 446.1 (M + 1) Method C 484 1H NMR (300 MHz, DMSO) δ12.82 (s, 1H), 9.67 (d, J = 2.1 Hz, 1H), 8.77 (dt, J = 8.1, 2.0 Hz, 1H),8.71 (dd, J = 4.8, 1.7 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.83 (s, 1H),7.60-7.53 (m, 3H), 7.48 (s, 1H), 7.20 (d, J = 2.6 Hz, 1H), 4.20 (q, J =6.9 Hz, 2H), 2.90 (d, J = 4.7 Hz, 3H), 1.44 (t, J = 6.9 Hz, 3H). DMSO 95Method G1 422.1 (M + 1) Method C 485 1H NMR (300 MHz, DMSO) δ 9.66 (s,1H), 9.44 (d, J = 1.4 Hz, 1H), 8.64-8.55 (m, 2H), 7.90 (s, 1H), 7.81 (d,J = 9.1 Hz, 1H), 7.76 (d, J = 2.5 Hz, 1H), 7.69 (s, 2H), 7.54-7.45 (m,2H), 4.19 (q, J = 7.0 Hz, 2H), 4.04 (s, 3H), 1.42 (t, J = 6.9 Hz, 3H).DMSO 99 Method G1 390.1 (M + 1) Method C 486 1H NMR (300 MHz, DMSO) δ9.57 (d, J = 1.5 Hz, 1H), 9.07 (d, J = 4.6 Hz, 1H), 8.94 (dd, J = 5.2,1.4 Hz, 1H), 8.04 (d, J = 9.1 Hz, 1H), 7.97 (dd, J = 6.7, 5.0 Hz, 1H),7.67 (dd, J = 9.1, 2.8 Hz, 1H), 7.55 (d, J = 2.7 Hz, 1H), 7.36 (dd, J =6.4, 2.3 Hz, 2H), 7.14-7.03 (m, 2H), 3.74 (s, 3H), 3.69 (s, 3H). DMSO 99Method G1 382.5 (M + 1) Method C 487 1H NMR (300 MHz, DMSO) δ 12.59 (s,1H), 9.58 (d, J = 2.0 Hz, 1H), 8.94 (d, J = 8.2 Hz, 1H), 8.84 (d, J =5.2 Hz, 1H), 8.73 (s, 1H), 8.09 (s, 1H), 7.95 (s, 3H), 7.82 (dd, J =8.4, 5.4 Hz, 2H), 7.75 (d, J = 7.4 Hz, 2H), 7.59-7.42 (m, 3H). DMSO 99Method G1 458.4 (M + 1) Method C 488 1H NMR (300 MHz, DMSO) δ 13.79 (s,1H), 9.49 (d, J = 1.5 Hz, 1H), 8.96 (d, J = 8.0 Hz, 1H), 8.86 (d, J =3.7 Hz, 1H), 7.95-7.71 (m, 4H), 7.65 (d, J = 1.6 Hz, 1H), 6.76 (s, 1H),2.85 (d, J = 22.5 Hz, 4H), 2.44-2.29 (m, 2H). DMSO 93 Method G1 422.4(M + 1) Method C 489 1H NMR (300 MHz, DMSO) δ 9.53 (d, J = 1.8 Hz, 1H),9.04 (d, J = 7.9 Hz, 1H), 8.93 (d, J = 3.9 Hz, 1H), 7.95 (dd, J = 8.0,5.2 Hz, 1H), 7.90-7.78 (m, 2H), 7.70 (d, J = 1.7 Hz, 1H), 2.29 (s, 3H),2.24 (s, 3H). DMSO 94 Method G1 410.3 (M + 1) Method C 490 1H NMR (300MHz, DMSO) δ 13.07 (s, 1H), 9.93 (d, J = 1.8 Hz, 1H), 9.64 (d, J = 1.6Hz, 1H), 8.90-8.78 (m, 1H), 8.76-8.62 (m, 2H), 8.29 (s, 1H), 8.18 (d, J= 8.3 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.71 (dd, J = 8.3, 1.9 Hz, 1H),7.65 (s, 1H), 7.57 (dd, J = 9.1, 2.5 Hz, 1H), 7.53-7.44 (m, 2H), 7.01(s, 1H), 4.21 (q, J = 6.9 Hz, 2H), 3.34 (s, 3H), 1.44 (t, J = 6.9 Hz,3H), DMSO 99 Method G1 464.2 (M + 1) Method C 491 1H NMR (300 MHz, DMSO)δ 9.78 (s, 1H), 9.50 (d, J = 2.0 Hz, 1H), 8.68-8.57 (m, 2H), 7.97 (d, J= 2.5 Hz, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 9.1 Hz, 1H),7.55-7.43 (m, 3H), 7.22 (d, J = 8.4 Hz, 1H), 4.22 (q, J = 6.9 Hz, 2H),3.37 (d, J = 4.3 Hz, 6H), 1.43 (t, J = 6.9 Hz, 3H). DMSO 99 Method G1427.5 (M + 1) Method C 492 1H NMR (300 MHz, DMSO) δ 11.48 (s, 1H), 10.97(s, 1H), 9.28 (d, J = 1.5 Hz, 1H), 8.64 (dd, J = 4.6, 1.7 Hz, 1H), 8.40(d, J = 8.1 Hz, 1H), 7.94-7.80 (m, 3H), 7.53-7.35 (m, 2H), 7.02 (t, J =7.5 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 4.04 (s, H). DMSO 99 Method F5,G13 391.1 (M + 1) Method C 493 1H NMR (300 MHz, DMSO) δ 11.28 (s, 1H),9.62 (d, J = 1.7 Hz, 1 H), 9.17 (d, J = 7.8 Hz, 1H), 8.93 (dd, J = 5.2,1.3 Hz, 1H), 8.60 (s, 1H), 8.05 (s, 1H), 8.03-7.94 (m, 2H), 7.77 (s,1H), 7.64 (dd, J = 9.2, 2.5 Hz 1H), 7.40 (d, J = 2.6 Hz, 1H), 3.97 (s,3H). DMSO 99 Method G14 362.4 (M + 1) Method C 494 ¹H-NMR (400 MHz,DMSO-d₆): δ 10.14 (s, 1H), 9.54 (s, 1H), 8.70-8.67 (m, 2H), 8.48 (s,1H), 8.16 (s, 1H), 7.96-7.89 (m, 3H), 7.60 (t, J = 8.0 Hz, 1H),7.55-7.52 (m, 1H), 7.17 (d, J = 8.8 Hz, 1H), 3.71 (s, 2H), 2.72-2.65 (m,8H). DMSO 95 Method G1 498.1 (M + 1) t = 2.128 min Method B (NH4HCO3)495 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.71 (s, 1H), 9.37 (s, 1H), 8.93 (s,1H), 8.67 (d, J = 3.2 Hz, 1H), 8.48 (d, J = 8.0 Hz, IH), 7.93 (s, 1H),7.39 (d, J = 8.0 Hz, 1H), 7.65 (m, 2H), 7.04 (d, J = 8.0 Hz, 1H), 2.95(t, J = 8.0 Hz, 2H), 2.64 (t, J = 8.0 Hz, 2H). DMSO 95 Method G1 402.0(M + 1) t = 1.746 min Method B (NH4HCO3) 496 ¹H-NMR (400 MHz, DMSO-d₆):δ 11.38 (s, 1H), 9.51 (s, 1H), 8.67-8.60 (m, 3H), 8.24-8.10 (m, 2H),7.88-7.83 (m, 2H), 7.58-7.55 (m, 3H), 7.33 (dd, J = 7.2, 4.8 Hz, 1H),3.97 (s, 3H). DMSO 95 Method J1 373.0 (M + 1) t = 1.523 min Method B(NH4HCO3) 497 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.92 (s, 1H), 9.30 (s, 1H),8.60 (d, J = 3.4 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 4.4 Hz,1H), 7.87 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.59-7.40 (m,5H), 4.24 (q, J = 6.9 Hz, 2H), 2.55 (d, J = 4.5 Hz, 3H), 1.45 (t, J =6.9 Hz, 3H). DMSO 95 Method G1 418.2 (M + 1) t = 1.782 min Method B(NH₄HCO₃) 498 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.14 (s, 1H), 9.54 (d, J =2.0 Hz, 1H), 8.70-8.67 (m, 2H), 8.50 (s, 1H), 8.15 (s, 1H), 7.94- 7.92(m, 3H), 7.61 (t, J = 8.0 Hz, 1H), 7.55 (dd, J = 8.0, 4.8 Hz, 1H), 7.18(d, J = 8.0 Hz, 1H), 3.90 (s, 2H), 3.17 (s, 4H), 2.98 (s, 4H). DMSO 95Method G1 530.0 (M + 1) t = 1.856 min Method B (NH₄HCO₃) 499 ¹H-NMR (400MHz, DMSO-d₆): δ 13.19 (s, 1H), 9.65 (s, 1H), 9.17 (d, J = 8.2 Hz, 1H),8.97 (d, J = 4.5 Hz, 1H), 8.93 (s, 1H), 8.81 (d, J = 8.2 Hz, 1H), 8.45(s, 1H), 8.40 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.99(dd, J = 16.0, 10.4 Hz, 3H), 7.74 (t, J = 7.4 Hz, 1H), 7.32 (t, J = 7.6Hz, 1H), 3.38 (s, 3H). DMSO 95 Method G1 420.1 (M + 1) t = 1.478 minMethod B (NH₄HCO₃) 501 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.46 (s, 1H), 9.46(s, 1H), 8.97 (d, J = 7.9 Hz, 1H), 8.93 (d, J = 4.4 Hz, 1H), 8.77 (d, J= 12.1 Hz, 1H), 8.55 (s, 1H), 8.16-7.91 (m, 4H), 7.83 (t, J = 7.5 Hz,1H), 7.73 (d, J = 9.3 Hz, 1H), 7.05 (t, J = 6.9 Hz, 1H). DMSO 95 MethodG1 378.1 (M + 1) t = 1.873 min Method B (NH₄HCO₃) 502 ¹H-NMR (400 MHz,DMSO-d₆): δ 13.00 (s, 1H), 9.83 (s, 1H), 9.17 (d, J = 8.0 Hz, 1H), 9.00(d, J = 8.0 Hz, 1H), 8.73-8.72 (m, 1H), 8.49 (s, 1H), 7.96 (d, J = 8.4Hz, 1H), 7.92 (s, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.63-7.53 (m, 3H), 7.28(d, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H). DMSO 95 Method G1 358.0(M + 1) t = 1.644 min Method B (NH₄HCO₃) 503 ¹H-NMR (400 MHz, DMSO-d₆):δ 11.34 (s, 1H), 9.50 (s, 1H), 8.69 (d, J = 3.6 Hz, 1H), 8.65 (d, J =7.6 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 8.10 (s, 1H),8.00-7.97 (m, 1H), 7.91-7.84 (m, 2H), 7.69-7.66 (m, 1H), 7.55-7.52 (m,1H), 7.16 (t, J = 9.2 Hz, 1H). DMSO 95 Method G1 378.0 (M + 1) t = 1.780min Method B (NH₄HCO₃) 504 1H-NMR (300 MHz, DMSO): δ 10.48 (s, 1H), 9.57(s, 1H), 9.13 (d, J = 7.6 Hz, 1H), 8.97-8.80 (m, 2H), 8.31 (s, 1H), 8.19(s, 1H), 8.10 (d, J = 6.5 Hz, 1H), 7.97 (d, J = 9.1 Hz, 2H), 7.83 (d, J= 7.7 Hz, 1H), 7.66 (t, J = 7.9 Hz, 2H), 7.47 (d, J = 5.4 Hz, 1H), 4.02(s, 3H). DMSO 95 Method G1 396.1 (M + 1) Method C 505 ¹H NMR (400 MHz,DMSO) δ 15.71 (s, 1H), 10.01 (s, 1H), 9.59-9.51 (m, 1H), 8.73-8.62 (m,2H), 8.60-8.54 (m, 1H), 8.13-7.96 (m, 2H), 7.93-7.82 (m, 2H), 7.62-7.49(m, 2H), 4.01 (s, 3H). DMSO >98 G1 506 ¹H NMR (400 MHz, DMSO) δ 10.77(s, 1H), 9.75 (s, 1H), 9.55-9.46 (m, 1H), 8.73-8.60 (m, 2H), 7.96 (d, J= 2.7 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.63 (m, J = 2.1 Hz, 1H),7.58-7.47 (m, 3H), 6.99 (d, J = 8.5 Hz, 1H), 4.64 (s, 2H), 3.97 (s, 3H).DMSO >98 G1 (0.1 N HCl added) 507 ¹H NMR (400 MHz, DMSO) δ 12.54 (s,1H), 9.85 (s, 1H), 9.51 (s, 1H), 8.70-8.60 (m, 2H), 8.27- 8.16 (m, 2H),8.03 (d, J = 2.5 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.72-7.59 (m, 2H),7.56-7.47 (m, 2H), 3.99 (s, 3H). DMSO >98 G1 508 ¹H NMR (400 MHz, DMSO)δ 9.87 (s, 1H), 9.50-9.47 (m, 1H), 8.66-8.61 (m, 2H), 8.21 (s, 1H), 8.16(d, J = 1.6 Hz, 1H), 8.02 (d, J = 2.7 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H),7.74 (dd, J = 8.7, 1.9 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.56-7.47 (m,2H), 3,99 (s, 3H), 3.90 (s, 3H). DMSO >98 G1 509 ¹H NMR (400 MHz, DMSO)δ 9.90 (s, 1H), 9.47 (dd, J = 2.1, 0.8 Hz, 1H), 8.67-8.60 (m, 2H), 8.15(d, J = 2.1 Hz, 1H), 7.97 (d, J = 2.7 Hz, 1H), 7.88-7.81 (m, 2H),7.57-7.49 (m, 2H), 7.44 (d, J = 8.7 Hz, 1H), 3.98 (s, 3H), 3.47 (s, 3H).DMSO >98 G1 (0.1 N HCl added) 510 ¹H NMR (400 MHz, DMSO) δ 10.76 (s,1H), 10.62 (s, 1H), 9.71 (s, 1H), 9.53-9.48 (m, 1H), 8.68-8.62 (m, 2H),7.98 (d, J = 2.6 Hz, 1H), 7.81 (d, J = 9.1 Hz, 1H), 7.63 (d, J = 1.8 Hz,1H), 7.55-7.49 (m, 2H), 7.37 (dd, J = 8.4, 2.0 Hz, 1H), 7.01 (d, J = 8.3Hz, 1H), 3.97 (s, 3H). DMSO >98 G1 (0.1 N HCl added) 511 ¹H NMR (400MHz, DMSO) δ 9.96 (s, 1H), 9.49 (dd, J = 2.1, 0.8 Hz, 1H), 8.79 (s, 1H),8.67-8.61 (m, 2H), 8.39-8.36 (m, 1H), 8.02 (d, J = 2.7 Hz, 1H), 7.90-7.84 (m, 3H), 7.56 (dd, J = 9.1, 2.7 Hz, 1H), 7.54-7.50 (m, 1H), 3.99(s, 3H). DMSO >98 J2 512 ¹H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 9.48(dd, J = 2.1, 0.8 Hz, 1H), 8.67-8.61 (m, 2H), 8.10-8.08 (m, 1H), 8.00(d, J = 2.7 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.65-7.63 (m, 2H), 7.57-7.49 (m, 2H), 4.22 (s, 3H), 3.99 (s, 3H). DMSO >98 G1 513 ¹H NMR (400MHz, DMSO) δ 9.92 (s, 1H), 9.49 (dd, J = 2.1, 0.8 Hz, 1H), 8.67-8.60 (m,2H), 8.22 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 2.7 Hz, 1H), 7.85 (d, J =9.1 Hz, 1H), 7.70-7.64 (m, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.57-7.49 (m,2H), 4.21 (s, 3H), 3.98 (s, 3H). DMSO >98 J2 514 ¹H NMR (400 MHz, DMSO)δ 10.97 (s, 1H), 9.43 (d, J = 1.6 Hz, 1H), 8.98-8.91 (m, 1H), 8.89 (dd,J = 5.2, 1.3 Hz, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 8.13-8.04 (m, 2H),7.92-7.85 (m, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.70-7.63 (m, 2H), 4.21 (s,3H), 4.02 (s, 3H). DMSO >98 G1 515 ¹H NMR (400 MHz, DMSO) δ 11.90 (s,1H), 10.45 (s, 1H), 9.46 (d, J = 1.7 Hz, 1H), 8.97-8.89 (m, 1H), 8.85(dd, J = 5.2, 1.5 Hz, 1H), 8.16-8.10 (m, 2H), 8.03-7.97 (m, 2H), 7.94(d, J = 9.1 Hz, 1H), 7.90-7.82 (m, 1H), 7.63 (dd, J = 9.1, 2.6 Hz, 1H),7.44 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 9.4 Hz, 1H), 4.00 (s, 3H).DMSO >98 G1 (0.1 N HCl added) 516 ¹H NMR (400 MHz, DMSO) δ 9.90 (s, 1H),9.53-9.50 (m, 1H), 8.68-8.63 (m, 2H), 8.27 (d, J = 2.0 Hz, 1H), 8.01 (d,J = 2.7 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H),7.81 (dd, J = 8.7, 2.1 Hz, 1H), 7.58-7.50 (m, 2H), 4.20 (s, 3H), 3.99(s, 3H). DMSO >98 G1 517 ¹H NMR (300 MHz, DMSO) δ 11.35 (s, 1H), 9.58(d, J = 1.6 Hz, 1H), 9.24 (d, J = 8.2 Hz, 1H), 9.05-8.97 (m, 1H),9.05-8.95 (m, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.11-8.02 (m, 3H), 7.90 (d,J = 7.8 Hz, 1H), 7.58 (dd, J = 8.8, 2.0 Hz, 2H), 7.52-7.46 (m, 1H), 7.28(s, 1H), 3.98 (d, J = 9.2 Hz, 3H). DMSO >98 G1 518 ¹H NMR (300 MHz,DMSO) δ 11.32 (s, 1H), 9.60 (s, 1H), 9.23 (d, J = 8.0 Hz, 1H), 8.98 (d,J = 5.4 Hz, 1H), 8.26 (s, 1H), 8.06 (dd, J = 13.2, 7.3 Hz, 2H), 7.63 (d,J = 9.1 Hz, 1H), 7.50-7.36 (m, 4H), 7.32 (s, 1H), 7.06-6.90 (m, 1H),3.99 (s, 3H), 3.86 (s, 3H). DMSO >98 G1 519 1H NMR (300 MHz, DMSO) δ13.17 (s, 1H), 11.46 (s, 1H), 9.19 (d, J = 1.7 Hz, 1H), 8.95-8.78 (m,2H), 8.31 (d, J = 2.6 Hz, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.86 (dd, J =7.9, 5.4 Hz, 1H), 7.77-7.54 (m, 3H), 7.44 (dd, J = 11.4, 3.9 Hz, 1H),7.20-7.02 (m, 1H), 4.01 (s, 3H). DMSO >98 G1 520 ¹H NMR (300 MHz, DMSO)δ 11.10 (s, 1H), 9.59 (d, J = 1.8 Hz, 1H), 9.15 (d, J = 8.0 Hz, 1H),8.93 (d, J = 3.9 Hz, 1H), 8.22 (d, J = 2.6 Hz, 1H), 7.99 (t, J = 7.4 Hz,2H), 7.72 (dd, J = 8.4, 4.7 Hz, 2H), 7.63-7.50 (m, 2H), 7.35 (s, 1H),7.27-7.18 (m, 1H), 3.99 (s, 3H). DMSO >98 G1 521 ¹H NMR (300 MHz, DMSO)δ 11.51 (s, 1H), 9.63 (d, J = 1.9 Hz, 1H), 9.18 (d, J = 8.1 Hz, 1H),8.98 (dd, J = 5.2, 1.2 Hz, 1H), 8.31 (d, J = 2.5 Hz, 1H), 8.17 (d, J =9.1 Hz, 1H), 8.01 (dd, J = 8.0, 5.3 Hz, 1H), 7.84 (dd, J = 7.7, 1.5 Hz,1H), 7.66 (dd, J = 9.1, 2.5 Hz, 1H), 7.48-7.35 (m, 2H), 7.21 (d, J = 8.2Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 3.99 (d, J = 6.3 Hz, 6H). DMSO >98 G11758 1H NMR (DMSO-d6) ppm 13.00-12.40 (br, 1H), 9.79 (d, J = 1.68 Hz,1H), 9.30 (d, J = 8.20 Hz, 1H), 8.95 (dd, J = 5.32, 1.44 Hz, 1H), 8.71(d, J = 4.24 Hz, 1H), 8.37 (brd, J = 2.56 Hz, 1H), 8.25-8.21 (m, 2H),8.11-8.02 (m, 2H), 7.98 (d, J = 9.12 Hz, 1H), 7.66 (dd, J = 9.12, 2.68Hz, 1H), 7.53-7.50 (m, 1H), 4.03 (s, 3H). The 1H of 3HCl was notobserved. DMSO >98 G13 1759 IH NMR (DMSO-d6) pprn 10.35 (br, 1H), 9.37(d, J = 1.6 Hz, 1H), 8.96 (d, J = 7.28 Hz, 1H), 8.90 (d, J = 4.2 Hz,1H), 8.04 (s, 1H), 7.98 (m, 1H), 7.95 (d, J = 9.16 Hz, 1H), 7.64 (dd, J= 9.16, 2.56 Hz, 1H), 6.18 (s, 1H), 3.98 (s, 3H), 3.66 (s, 3H), 2.24 (s,3H). The 1H of 3HCl was not observed. DMSO >98 J2

Method K: 2-Amino-5-methoxybenzoic acid (viii-a)

5-Methoxy-2-nitrobenzoic acid (30.0 g, 152.2 mmol) was hydrogenated overPd/C (10% c, 300 mg) in THF (250 mL) at room temperature under H₂balloon. The mixture was stirred for 18 h. After the reaction wascompleted, the catalyst was removed by filtration over Celite and thefiltrate was concentrated to afford 25.0 g of 2-amino-5-methoxybenzoicacid as a brown solid (98%). LCMS m/z=168.1 (M+1), 150.1 (M−17) (MethodB) (retention time=0.53 min) ¹H NMR (400 MHz, DMSO-d₆): δ 7.31 (d, J=2.8Hz, 1H), 6.61 (dd, J=8.8, 3.2 Hz, 1H), 6.44 (d, J=8.8 Hz, 1H), 3.60 (s,3H).

Method H: 6-Methoxyquinazoline-2,4(1H, 3H)-dione (ix-a)

2-Amino-5-methoxybenzoic acid (13.0 g, 77.8 mmol, 1.0 eq.) was suspendedin water (200 mL) and glacial acetic acid (5.2 mL) at 35° C. A freshlyprepared solution of potassium cyanate (8.21 g, 101.4 mmol, 1.3 eq.) inwater (86 mL) was added dropwise to the stirred mixture. After 4 h, NaOH(104.0 g, 2600 mL, 33.4 eq.) was added in portions, keeping the reactiontemperature below 40° C. A clear solution was obtained momentarilybefore a precipitate formed. After cooling, the precipitate was filteredoff and dissolved in hot water which was acidified to pH 5. Theprecipitate was collected and washed with water, dried by lyophilizationto afford 9.63 g of 6-methoxyquinazoline-2,4(1H, 3H)-dione as a whitesolid (65%). LCMS m/z=193.1 (M+1) (Method B) (retention time=1.22 min).¹H NMR (400 MHz, DMSO-d₆): δ 11.26 (s, 1H), 11.01 (s, 1H), 7.31-7.25 (m,2H), 7.10 (d, 1H, J=8.8 Hz), 3.77 (s, 3H).

Method F1: 2,4-Dichloro-6-methoxyquinazoline (x-a)

To a mixture of 6-methoxyquinazoline-2,4(1H, 3H)-dione (9.63 g, 50.2mmol) in POCl₃ (150 mL) was added N,N-dimethylaniline (0.5 mL). Theresulting mixture was stirred at 120° C. for 2 h. After the reaction wascompleted, POCl₃ was removed in vacuo, and the residue was added toice-water slowly. The pH was adjusted to ˜7 by slowly adding NaHCO₃(sat.) at 0° C., then a precipitate formed. The solid was collected anddried in vacuo to give 11.2 g of 2,4-dichloro-6-methoxyquinazoline in a98% yield as a brown solid. LCMS m/z=229.1, 231.0 (M+1) (Method B)(retention time=1.87 min). ¹H-NMR (400 MHz, DMSO-d₆): δ 7.89 (d, J=9.2Hz, 1H), 7.71 (dd, J=8.8, 2.4 Hz, 1H), 7.38 (d, J=1.6 Hz, 1H), 3.91 (s,3H).

Method M: 2-Chloro-6-methoxyquinazolin-4-ol (xi-a)

A mixture of 2,4-dichloro-6-methoxyquinazoline (4.20 g, 18.5 mmol, 1.0eq.) in THF (60 mL) and 1120 (60 mL) was treated with NaOH (4.00 g, 100mmol, 5.4 eq.). The resulting mixture was stirred at 40° C. for 2 h. Thereaction color turned to dark green and then a precipitate formed. Afterthe reaction was completed, the mixture was cooled to room temperature.The precipitate was filtered off and the filtrate was concentrated downto 60 mL. The pH was then adjusted to 6 by adding 2N HCl in water. Theprecipitate which formed was collected and dried in vacuo to give 4.00 gof 2-chloro-6-methoxyquinazolin-4-ol as a grey solid (98%). LCMSm/z=211.1, 213.0 (M+1) (Method B) (retention time=1.11 min).

Method N: 6-Methoxy-2-(pyridin-3-yl) quinazolin-4-ol (xii-a)

To a mixture of 2-chloro-6-methoxyquinazolin-4-ol (1.20 g, 5.7 mmol, 1.0eq.), pyridin-3-ylboronic acid (1.27 g, 8.6 mmol, 1.5 eq.), K₂ CO₃ (2.37g, 17.1 mmol, 3.0 eq.) in dioxane (100 mL) and 1H₂O (10 ml) was addedPd(PPh₃)₂Cl₂ (230 mg, 0.29 mmol, 0.05 eq.) under N₂ atmosphere. Theresulting mixture was stirred at 105° C. under N₂ atmosphere overnight.After reaction was completed, the mixture was cooled to roomtemperature, and the resultant precipitate was removed by filtration.The filtrate was concentrated in vacuo and the residue was partitionedbetween H₂O (30 mL) and ethyl acetate (100 mL×3). The combined organiclayers were washed with brine, dried over MgSO₄. After filtration andevaporation, the crude product was obtained, which was combined with thefilter cake and dried in vacuo to give 1.35 g of6-methoxy-2-(pyridin-3-yl) quinazolin-4-ol as a gray solid. LCMSm/z=254.1 (M+1) (Method B) (retention time=1.39 min). The crude productwas used for the next step without further purification.

Method F1: 4-Chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (xiii-a)

To a mixture of 6-methoxy-2-(pyridin-3-yl) quinazolin-4-ol (600 mg, 2.37mmol) in POCl₃ (5 mL) was added N,N-dimethyl aniline (1 drop). Theresulting mixture was stirred at 120° C. for 30 min. After the reactionwas completed, POCl₃ was removed in vacuo, and the residue was added toice-water slowly. The pH was adjusted to ˜7 by slowly adding NaHCO₃(sat.) at 0° C. and then a precipitate formed. The solid was collectedand was purified by chromatography on silica gel eluted with petroleumether/ethyl acetate (v/v=4:1 to 1:1) to give 260 mg of4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline as a pale yellow solid(40.4%). LCMS m/z=272.1, 274.0 (M+1) (Method B) (retention time=1.90min).

Method G1:N-(2-Fluorophenyl)-6-methoxy-2-(pyridin-3-yl)quinazolin-4-amine (xiv-a)

A mixture of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (80 mg,0.293 mmol, 1.0 eq.) and 2-fluoroaniline (65 mg, 0.58 mmol, 2 eq.) ini-PrOH (5 mL) was stirred at 85° C. for 18 h. After the reaction wascompleted, the mixture was filtered, and the filter cake was washed withH₂O (10 ml) and diethyl ether (10 mL). After drying, the crude productwas purified by PREP-HPLC (Condition C: Gradient: B=5%-50%, Target Peak:at 7.2 min) to give 16.5 mg ofN-(2-fluorophenyl)-6-methoxy-2-(pyridin-3-yl)quinazolin-4-amine as ayellow solid, yield 16.4%. LCMS m/z=347.0 (M+1) (Method A) (retentiontime=1.31 min). ¹H-NMR (400 MHz, DMSO-d₆): δ 10.08 (s, 1H), 9.33 (s,1H), 8.72 (d, J=4.4 Hz, 1H), 8.66 (d, J=8.0 Hz, 1H), 8.80 (d, J=1.2 Hz,1H), 7.88 (d, J=9.2 Hz, 1H), 7.70-7.65 (m, 2H), 7.58 (dd, J=8.8, 1.2 Hz,1H), 7.44-7.35 (m, 3H), 3.97 (s, 3H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 6 substituting with appropriate nitrobenzoic acid, boronic acid and aniline

TABLE 2 Molec- Num- Salt ular ber Product type Mass ¹H-NMR 522

455.34 1H-NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 9.52-9.51 (m, 1H),8.63-8.66 (m, 2H), 8.32 (d, J = 2.4 Hz, 1H), 7.94- 7.91 (m, 2H), 7.72(d, J = 8.3 Hz, 1H), 7.54 (q, J = 3.2 Hz, 1H), 7.32 (s, 1H), 4.87-4.90(m, 1H), 3.96 (s, 3H), 1.38 (d, J = 6.0 Hz, 6H). 523

438.88 1H-NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 9.49 (d, J = 2.0 Hz,1H), 8.60- 8.66 (m, 2H), 8.18 (dd, J = 6.4, 2.4 Hz, 1H), 7.84-7.88 (m,2H), 7.50-7.54 (m, 2H), 7.31 (s, 1H), 4.85-4.88 (m, 1H), 3.96 (s, 3H),1.38 (d, J = 6.4 Hz, 6H). 524

422.43 1H-NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 9.48 (s, 1H),8.60-8.65 (m, 2H), 8.04-8.10 (m, 1H), 7.92 (s, 1H), 7.49- 7.66 (m, 3H),7.30 (s, 1H), 4.86-4.92 (m, 1H), 3.96 (s, 3H), 1.37 (d, J = 6.0 Hz, 6H)525

HCl 429.47 1H-NMR (400 MHz, DMSO-d6): δ 12.96 (s, 1H), 9.60 (d, J = 8.0Hz, 1H), 9.14 (d, J = 8.0 Hz, 1H), 8.68-8.74 (m, 2H), 8.46 (s, 1H),7.95-7.96 (m, 2H), 7.74- 7.70 (m, 1H), 7.59-7.54 (m, 2H), 7.36 (s, 1H),7.19-7.15 (m, 1H), 4.76-4.82 (m, 1H), 3.99 (s, 3H), 1.44 (d, J = 6.0 Hz,6H). 526

452.45 1H-NMR (400 MHz, DMSO-d6): δ 9.70 (s, 1H), 9.52-9.53 (m, 1H),8.64-8.67 (m, 2H), 7.89-7.94 (m, 2H), 7.73-7.74 (m, 1H), 7.48-7.53 (m,3H), 7.32 (t, J = 83.6 Hz, 1H), 6.96-6.99 (m, 1H), 4.89- 4.92 (m, 1H),3.98 (s, 3H), 1.38 (d, J = 6.0 Hz, 6H). 527

455.34 1H-NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 9.52 (d, J = 1.6 Hz,1H), 8.64- 8.68 (m, 2H), 8.12-8.13 (m, 2H), 7.90 (s, 1H), 7.54-7.58 (m,1H), 7.34-7.36 (m, 2H), 4.86-4.92 (m, 1H), 3.98 (s, 3H), 1.40 (d, J =6.0 Hz, 6H). 528

455.34 1H-NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 9.52 (d, J = 1.2 Hz,1H), 8.64- 8.67 (m, 2H), 8.32 (d, J = 2.8 Hz, 1H), 7.94 (dd, J = 6.8,2.4 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.53-7.56 (m, 1H),7.32 (s, 1H), 4.14 (t, J = 6.4 Hz, 2H), 3.99 (s, 3H), 1.85-1.92 (m, 2H),1.06 (t, J = 7.2 Hz, 3H). 529

438.88 1H-NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1H), 9.50 (d, J = 1.6 Hz,1H), 8.62- 8.66 (m, 2H), 8.20 (dd, J = 6.4, 2.4 Hz, 1H), 7.85-7.89 (m,2H), 7.50-7.55 (m, 2H), 7.31 (s, 1H), 4.13 (t, J = 6.4 Hz, 2H), 3.98 (s,3H), 1.82-1.90 (m, 2H), 1.06 (t, J = 7.6 Hz, 3H). 530

422.43 1H-NMR (400 MHz, DMSO-d6): δ 9.74- 9.76 (m, 1H), 9.52 (d, J = 1.6Hz, 1H), 8.64-8.69 (m, 2H), 8.08-8.14 (m, 1H), 7.90 (s, 1H), 7.68-7.70(m, 1H), 7.52- 7.60 (m, 2H), 7.34 (s, 1H), 4.16 (t, J = 6.4 Hz, 2H),4.01 (s, 3H), 1.85-1.94 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H). 531

HCl 429.47 1H-NMR (400 MHz, DMSO-d6): δ 12.86 (s, 1H), 9.59 (d, J = 1.6Hz, 1H), 9.05 (d, J = 8.4 Hz, 1H), 8.85 (d, J = 8.0 Hz, 1H), 8.76-8.78(m, 1H), 8.44 (s, 1H), 7.96 (dd, J = 8.0, 1.6 Hz, 2H), 7.70-7.73 (m,2H), 7.53 (s, 1H), 7.37 (s, 1H), 6.96- 7.22 (m, 1H), 4.16 (t, J = 6.4Hz, 2H), 4.01 (s, 3H), 1.86-1.90 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H). 532

452.45 1H-NMR (400 MHz, DMSO-d6): δ 9.67 (s, 1H), 9.50 (d, J = 4.0 Hz,1H), 8.62- 8.65 (m, 2H), 7.89-7.92 (m, 3H), 7.44- 7.54 (m, 1H),7.29-7.31 (m, 3H), 7.26 (t, J = 74.0 Hz, 1H), 4.14 (t, J = 6.8 Hz, 2H),3.98 (s, 3H), 1.84-1.90 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H). 533

HCl 454.88 1H-NMR (400 MHz, DMSO-d6): δ 9.73 (s, 1H), 9.50 (d, J = 2.4Hz, 1H), 8.62- 8.67 (m, 2H), 8.20 (dd, J = 7.2 Hz, 2.8 Hz, 1H),7.85-7.89 (m, 2H), 7.51-7.57 (m, 2H), 7.33 (s, 1H), 4.31 (t, J = 4.0 Hz,2H), 3.99 (s, 3H) 3.80 (t, J = 4.8 Hz, 2H), 3.37 (s, 3H). 534

445.47 1H-NMR (400 MHz, CD3OD): δ 9.34 (s, 1H), 8.92 (d, J = 6.0 Hz,1H), 8.73 (m, 2H), 7.84 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.54 (t, J =8.0 Hz, 1H), 7.32 (s, 1H), 7.15 (s, 2H), 4.21 (s, 2H), 3.92 (s, 3H),3.78 (t, J = 4.4 Hz, 2H), 3.40 (s, 3H). 535

HCl 468.45 1H-NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1H), 9.53 (s, 1H), 8.66(d, J = 5.6 Hz, 2H), 7.91 (d, J = 6.4 Hz, 2H), 7.75 (d, J = 7.2 Hz, 1H),7.51 (dd, J = 7.6 Hz, 2H), 7.34 (s, 1H), 7.30 (t, J = 74.0 Hz, 1H), 6.97(dd, J = 8.0, 2.0 Hz, 1H), 4.32 (t, J = 4.4 Hz, 2H), 3.99 (s, 3H), 3.80(t, J = 4.4 Hz, 2H), 3.37 (s, 3H). 536

468.91 1H-NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.47 (s, 1H), 8.96(d, J = 6.4 Hz, 1H), 8.90 (d, J = 5.2 Hz, 1H), 8.11 (dd, J = 6.8 Hz, 2.4Hz, 1H), 8.05 (s, 2H), 7.85- 7.94 (m, 2H), 7.55 (t, J = 9.2 Hz, 1H),7.47 (s, 1H) 4.26 (t, J = 6.4 Hz, 2H), 4.01 (s, 3H), 3.55 (t, J = 6.0Hz, 2H), 3.29 (s, 3H), 2.06-2.13 (m, 2H). 537

397.26 1H-NMR (400 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.54 (s, 1H), 8.76(s, 2H), 8.49 (d, J = 7.0 Hz, 1H), 8.36 (s, 1H), 7.95 (d, J = 7.5 Hz,1H), 7.66-7.23 (m, 2H), 7.33 (s, 2H), 3.98 (s, 3H). 538

397.26 1H-NMR (400 MHz, DMSO-d6): 10.00 (s, 1H), 8.54 (d, J = 1.3 Hz,1H), 8.71- 8.56 (m, 2H), 8.47 (d, J = 9.2 Hz, 1H), 8.17 (s, 1H), 8.16(s, 1H), 7.59-7.56 (m, 1H), 7.35-7.30 (m, 3H), 3.98 (s, 3H). 539

364.35 1H-NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 9.53 (d, J = 1.6 Hz,1H), 8.70- 8.65 (m, 2H), 8.47 (d, J = 8.4 Hz, 1H), 8.12 (ddd, J = 13.2,7.6, 2.8 Hz, 1H), 7.72-7.70 (m, 1H), 7.58-7.49 (m, 2H), 7.32-7.27 (m,2H), 3.97 (s, 3H). 540

353.38 1H-NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 9.53 (d, J = 1.6 Hz,1H), 8.71- 8.66 (m, 2H), 8.50-8.43 (m, 2H), 8.26- 8.24 (m, 1M),7.70-7.54 (m, 3H), 7.34- 7.30 (m, 2H), 3.98 (s, 3H), 541

394.37 1H-NMR (400 MHz, DMSO-d6): δ 9.93 (s, 1H), 9.54 (s, 1H), 8.68 (d,J = 5.2 Hz, 2H), 8.51 (d, J = 9.2 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J =7.6 Hz, 1H), 7.55-7.10 (m, 5H), 6.96 (dd, J = 8.0, 2.0 Hz, 1H), 3.96 (s,3H). 542

371.39 1H-NMR (400 MHz, DMSO-d6): δ 12.97 (s, 1H), 9.60 (s, 1H), 9.10(d, J = 8.4 Hz, 1H), 8.75-8.71 (m, 2H), 8.48 (s, 1H), 8.07 (d, J = 9.6Hz, 1H), 7.95-7.90 (m, 2H), 7.74-7.70 (m, 1H), 7.58 (dd, J = 8.0, 4.8Hz, 1H), 7.35-7.33 (m, 2H), 7.19 (t, J = 7.2 Hz, 1H), 3.97 (s, 3H). 543

431.7 1H-NMR (400 MHz, DMSO-d6): δ 10.03 (s, 1H), 9.49-9.48 (m, 1H),8.69-8.67 (m, 1H), 8.63-8.59 9m, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.04 (s,1H), 8.00 (s, 1H), 7.93-7.90 (m, 1H), 7.74 (d, J = 8.8 Hz, 1H),7.56-7.53 (m, 1H), 4.07 (s, 3H). 544

431.7 1H-NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 9.46 (d, J = 3.2 Hz,1H), 8.68 (dd, J = 4.8, 2.0 Hz, 1H), 8.60-8.57 (m, 1H), 8.09 (s, 1H),8.08 (s, 1H), 7.97 (s, 2H), 7.54 (dd, J = 8.8, 4.8 Hz, 1H), 7.38 (t, J =2.0 Hz, 1H), 4.05 (s, 3H). 545

415.25 1H-NMR (400 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.47 (s, 1H),8.70-8.62 (m, 2H), 8.19-8.17 (m, 1H), 8.04 (s, 1H), 8 00 (s, 1H),7.84-7.88 (m, 1H), 7.59-7.53 (m, 2H), 4.07 (s, 3H). 546

398.79 1H-NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 9.47 (d, J = 1.6 Hz,1H), 8.69- 8.67 (m, 1H), 8.62-8.59 (m, 1H), 8.08- 8.04 (m, 2H), 8.00 (s,1H), 7.65-7.53 (m, 3H), 4.07 (s, 3H). 547

428.82 1H-NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.45 (d, J = 1.2 Hz,1H), 8.89 (d, J = 8.0 Hz, 1H), 8.83 (d, J = 4.0 Hz, 1H), 8.21 (s, 1H),8.00 (s, 1H), 7.85-7.78 (m, 3H), 7.55-7.51 (m, 1H), 7.31 (t, J = 72.8Hz, 1H), 7.05-7.03 (m, 1H), 4.07 (s, 3H). 548

387.82 1H-NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 9.38 (s, 1H),8.97-8.90 (m, 2H), 8.32-8.26 (m, 3H), 7.97-7.94 (m, 2H), 7.69-7.65 (m,2H), 4.08 (s, 3H). 549

405.84 1H-NMR (400 MHz, DMSO-d6): δ 12.98 (s, 1H), 9.36 (s, 1H),8.94-8.77 (m, 3H), 8.48 (s, 1H), 7.98-7.83 (m, 4H), 7.59- 7.14 (m, 2H),7.17 (s, 1H), 3.96 (s, 3H). 550

436.12 1H-NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 9.39 (s, 1H), 8.87(s, 1H), 8.81 (d, J = 4.4 Hz, 1H), 8.73 (d, J = 8.0 Hz, 1H), 8.24 (s,1H), 8.01 (s, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.76-7.73 (m, 1H), 7.66 (d,J = 8.8 Hz, 1H). 551

410.26 1H-NMR (400 MHz, DMSO-d6): δ 13.15 (s, 1H), 9.46 (s, 1H), 8.87(d, J = 8.4 Hz, 1H), 8.74 (d, J = 3.6 Hz, 1H), 8.68 (d, J = 7.2 Hz, 1H),8.49 (s, 1H), 8.23 (s, 1H), 8.02 (s, 2H), 7.94 (d, J = 8.0 Hz, 1H),7.69-7.61 (m, 2H), 7.23-7.20 (m, 1H). 552

433.24 1H-NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 9.53 (s, 1H), 9.02(s, 1H), 8.83- 8.80 (m, 2H), 8.20 (s, 1H), 7.91 (s, 1H), 7.81-7.79 (m,1H), 7.74-7.71 (m, 1H), 7.56-7.52 (m, 1H), 7.30 (t, J = 73.6 Hz, 1H),7.05 (d, J = 8.8 Hz, 1H). 553

419.67 1H-NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 9.40 (s, 1H), 8.97(s, 1H), 8.89- 8.85 (m, 2H), 8.15-8.14 (m, 1H), 8.05 (s, 1H), 7.89-7.87(m, 2H), 7.51-7.47 (m, 1H). 554

403.21 1H-NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 9.40 (s, 1H), 8.96(s, 1H), 8.84- 8.89 (m, 2H), 8.04-8.00 (m, 2H), 7.88 (s, 1H), 7.69-7.67(m, 1H), 7.54-7.47 (m, 1H). 555

436.12 1H-NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 8.28 (s, 1H), 8.88(d, J = 4.8 Hz, 1H), 8.85 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H), 7.97 (s,1H), 7.96 (s, 1H), 7.90- 7.86 (m, 2H), 7.29 (s, 1H). 556

441.31 1H-NMR (400 MHz, DMSO-d6): δ 9.74 (s, 1H), 9.50 (s, 1H),8.66-8.64 (m, 2H), 8.31 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H),7.68 (d, J = 8.8 Hz, 1H), 7.52 (dd, J = 7.4, 5.0 Hz, 1H), 7.29 (s, 1H),4.22 (q, J = 6.8 Hz, 2H), 3.97 (s, 3H), 1.45 (t, J = 6.8 Hz, 3H). 557

424.86 1H-NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.48 (s, 1H), 8.74-8.73(m, 2H), 8.18-8.16 (m, 1H), 7.90-7.85 (m, 2H), 7.67-7.65 (m, 1H), 7.53(t, J = 9 Hz, 1H), 7.33 (s, 1H), 4.24 (q, J = 7.2 Hz, 2H), 3.98 (s, 3H),1.46 (t, J = 7.2 Hz, 3H). 558

408.4 1H-NMR (400 MHz, DMSO-d6): δ 9.68 (s, 1H), 9.49 (s, 1H), 8.66-8.61(m, 2H), 8.10-8.04 (m, 1H), 7.84 (s, 1H), 7.66- 7.64 (m, 1H), 7.56-7.49(m, 2H), 7.30 (s, 1H), 4.23 (q, J = 6.8 Hz, 2H), 3.98 (s, 3H), 1.46 (t,J = 6.8 Hz, 3H). 559

397.43 1H-NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 9.43 (s, 1H),8.82-8.78 (m, 2H), 8.32 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.98 (s, 1H),7.77-7.73 (m, 1H), 7.68- 7.60 (m, 2H), 7.35 (s, 1H), 4.23 (q, J = 6.8Hz, 2H), 3.96 (s, 3H), 1.44 (t, J = 6.8 Hz, 3H). 560

410.83 1H-NMR (400 MHz, DMSO-d6): δ 9.89 (s, 1H), 9.48 (s, 1H), 8.74 (d,J = 6.0 Hz, 2H), 8.16 (dd, J = 6.8, 2.4 Hz, 1H), 7.85- 7.88 (m, 2H),7.67 (t, J = 6.4 Hz, 1H), 7.53 (t, J = 8.7 Hz, 1H), 7.32 (s, 1H), 3.93(s, 6H). 561

394.37 1H-NMR (400 MHz, DMSO-d6): δ 9.92 (s, 1H), 9.49 (s, 1H), 8.77 (d,J = 6.4 Hz, 2H), 8.02-8.08 (m, 1H), 7.90 (s, 1H), 7.70-7.74 (m, 1H),7.64-7.66 (m, 1H), 7.52-7.59 (m, 1H), 7.33 (s, 1H), 3.99 (s, 3H), 3.98(s, 3H). 562

383.4 1H-NMR (400 MHz, DMSO-d6): δ 9.87 (s, 1H), 9.50 (d, J = 1.6 Hz,1H), 8.63- 8.68 (m, 2H), 8.38 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.89(s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.52- 7.56(m, 1H), 7.33 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H). 563

427.28 1H-NMR (400 MHz, DMSO-d6): δ 9.70 (s, 1H), 9.50 (d, J = 1.6 Hz,1H), 8.66 (d, J = 4.8 Hz, 1H), 8.62 (d, J = 8.0 Hz, 1H), 8.11 (d, J =1.2 Hz, 2H), 7.73 (s, 1H), 7.53 (dd, J = 7.6, 4.8 Hz, 1H), 7.31 (s, 1H),7.28 (s, 1H), 3.97 (s, 6H). 564

2 HCl 389.3824 1H-NMR (400 MHz, DMSO-d6): δ 13.08 (s, 1H), 9.40 (s, 1H),8.86 (d, J = 8.1 Hz, 1H), 8.78 (s, 1H), 8.53 (d, J = 10.0 Hz, 1H), 8.46(s, 1H), 8.03 (d, J = 8.7 Hz, 1H), 8.00-7.88 (m, 2H), 7.73 (t, J = 7.8Hz, 1H), 7.66 (d, J = 10.3 Hz, 2H), 7.28 (t, J = 7.6 Hz, 1H), 3.99 (s,3H). 565

2 HCl 401.4180 1H-NMR (400 MHz, CD3OD): δ 9.20 (s, 1H), 8.85 (s, 1H),8.78 (s, 1H), 8.72 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.95(d, J = 7.7 Hz, 1H), 7.77-7.67 (m, 3H), 7.39 (t, J = 7.6 Hz, 1H), 4.18(s, 3H), 4.08 (s, 3H). Num- ¹H-NMR LCMS Purity Method for ber SolventLCMS Protocol Percent Coupling 522 DMSO 454.9, 457.0 (M + 1), 228.8(M/2 + 1) Method A (TFA) 95 Method N, G1 523 DMSO 439.1, 441.1 (M + 1),220.1, 220.8 (M/2 + 1) Method A (TFA) 95 Method N, G1 524 DMSO 423.2(M + 1), 212.2 (M/2 + 1) Method A (TFA) 95 Method N, G1 525 DMSO 430.2(M + 1) 215.7 (M/2 + 1) Method A (TFA) 95 Method N, G1 526 DMSO 453.1(M + 1) Method B (NH4HCO3) 95 Method N, G1 527 DMSO 455.0, 457.0 (M + 1)Method B (NH4HCO3) 95 Method N, G1 528 DMSO 455.1, 457.1 (M + 1) 229.1(M/2 + 1) Method A (TFA) 95 Method N, G1 529 DMSO 439.1, 441.1 (M + 1)220.1, 220.8 (M/2 + 1) Method A (TFA) 95 Method N, G1 530 DMSO 423.0(M + 1) 445.0 (M + 23) 212.1 (M/2 + 1) Method A (TFA) 95 Method N, G1531 DMSO 430.1 (M + 1) Method B (NH4HCO3) 95 Method N, G1 532 DMSO 453.1(M + 1) 227.2 (M/2 + 1) Method A (TFA) 95 Method N, G1 533 DMSO 455.1,457.1 (M + 1) Method B (NH4HCO3) 95 Method N, G1 534 CD3OD 446.2, 447.2(M + 1) Method B (NH4HCO3) 95 Method N, G1 535 DMSO 469.1 (M + 1) MethodB (NH4HCO3) 95 Method N, G1 536 DMSO 469.0, 471.0 (M + 1) 234.9, 235.6(M/2 + 1) Method A (TFA) 95 Method N, G1 537 DMSO 397.1, 399.0 (M + 1)Method B (NH4HCO3) 95 Method N, G1 538 DMSO 397.0, 399.0 (M + 1) MethodB (NH4HCO3) 95 Method N, G1 539 DMSO 365.2 (M + 1) Method B (NH4HCO3) 95Method N, G1 540 DMSO 354.2 (M + 1) Method B (NH4HCO3) 95 Method N, G1541 DMSO 395.1 (M + 1) Method B (NH4HCO3) 95 Method N, G1 542 DMSO 372.1(M + 1) Method B (NH4HCO3) 95 Method N, G1 543 DMSO 430.9, 432.9, 434.9(M + 1) Method B (NH4HCO3) 95 Method N, G1 544 DMSO 430.9, 432.9, 434.9(M + 1) Method B (NH4HCO3) 95 Method N, G1 545 DMSO 415.1, 417.0, 419.0(M + 1) Method B (NH4HCO3) 95 Method N, G1 546 DMSO 399.1, 401.1 (M + 1)Method B (NH4HCO3) 95 Method N, G1 547 DMSO 429.1, 431.1 (M + 1) MethodB (NH4HCO3) 95 Method N, G1 548 DMSO 387.9, 390.0 (M + 1) Method B(NH4HCO3) 95 Method N, G1 549 DMSO 405.9, 408.0 (M + 1) Method B(NH4HCO3) 95 Method N, G1 550 DMSO 434.9, 436.9, 438.8 (M + 1) Method B(NH4HCO3) 95 Method N, G1 551 DMSO 410.0, 412.0, 413.9 (M + 1) 432.0(M + 22) Method A (TFA) 95 Method N, G1 552 DMSO 432.9, 434.9 (M + 1)Method B (NH4HCO3) 95 Method N, G1 553 DMSO 419.0, 421.0, 423.0 (M + 1)Method B (NH4HCO3) 95 Method N, G1 554 DMSO 402.9, 404.9 (M + 1) MethodB (NH4HCO3) 95 Method N, G1 555 DMSO 434.9, 436.9, 438.9 (M + 1) MethodA (TFA) 95 Method N, G1 556 DMSO 441.0, 443.0 (M + 1) Method B (NH4HCO3)95 Method N, G1 557 DMSO 425.0, 427.0 (M + 1) Method B (NH4HCO3) 95Method N, G1 558 DMSO 409.0 (M + 1) Method B (NH4HCO3) 95 Method N, G1559 DMSO 398.1 (M + 1) Method B (NH4HCO3) 95 Method N, G1 560 DMSO411.1, 413.1 (M + 1) Method A (TFA) 95 Method N, G1 561 DMSO 395.0(M + 1) 198.1 (M/2 + 1) Method A (TFA) 95 Method N, G1 562 DMSO 384.2(M + 1) Method B (NH4HCO3) 95 Method N, G1 563 DMSO 427.1, 429.1, 431.0(M + 1) Method B (NH4HCO3) 95 Method N, G1 564 DMSO 390.0 (M + 1) MethodB (NH4HCO3) 95 Method N, G1 565 MeOD 402.1 (M + 1) Method B (NH4HCO3) 95Method N, G1

Method O1: CuI/Pd(PPh₃)₂Cl₂/Et₃N/DMF/rt

-   -   O2: Propargyl bromide/CuI/Pd(PPh₃)₂C₂/Nucleophile/DMF/rt    -   O3: Pd(OAc)₂/PPh₃/TBAB/piperidine/THF-H₂O/rt

Method O1:6-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine(xv-a)

A suspension ofN-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amine(synthesized as described in Scheme 1 and 4, substituting5-iodo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and3-chloro-4-fluoroaniline for 2-aminobenzamide) (1.00 g, 2.10 mmol),tert-butyldimethyl(2-propynyloxy)silane (0.85 ml, 4.20 mmol), copper(I)iodide (4.0 mg, 0.021 mmol), dichlorobis(triphenylphosphine) palladium(II) (Pd(PPh₃)₂Cl₂) (29 mg, 0.042 mmol), and triethylamine (1.17 ml,8.39 mmol) in DMF (15 mL) was stirred overnight at room temperatureunder argon atmosphere. Water (30 mL) and ethyl acetate (30 mL) wereadded to the mixture. The resultant precipitate was removed byfiltration. The filtrate was extracted with EtOAc (2×50 mL). Thecombined organic layer was washed with water (1×100 mL) and brine (1×100mL) and was dried over Na₂SO₄. After filtration and evaporation, thecrude product was obtained, which was purified by column chromatographyon silica gel (eluted with hexane/ethyl acetate 6:1 to 1:3) to give 0.73g of6-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amineas light brown solid (67%). LCMS m/z=519 (M+1) (Method D) (retentiontime=3.22 min). ¹H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.35 (s, 1H),8.62-8.44 (m, 3H), 8.11 (dd, J=6.8, 2.6 Hz, 1H), 7.76-7.66 (m, 3H),7.45-7.30 (m, 2H), 4.48 (s, 2H), 0.75 (s, 9H), 0.16 (s, 6H).

Method P:6-(3-(tert-butyldimethylsilyloxy)propyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine(xvi-a)

A suspension of 6-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine(0.20 g, 0.39 mmol) and 5% Pd—S—C (40 mg) in EtOAc (5 mL) and MeOH (5mL) was stirred overnight at room temperature under hydrogen atmosphere.The reaction mixture was filtered through Celite. The filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (eluted with hexane/ethyl acetate 6:1 to 2:3) to give 0.15g of6-(3-(tert-butyldimethylsilyloxy)propyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amineas yellow solid (74%). LCMS m/z=523 (M+1) (Method D) (retentiontime=3.35 min). ¹H NMR (300 MHz, CDCl₃) δ 9.69 (dd, J=2.2, 0.8 Hz, 1H),8.79-8.65 (m, 2H), 8.07 (dd, J=6.5, 2.7 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H),7.76-7.61 (m, 3H), 7.47-7.37 (m, 2H), 7.31-7.18 (m, 1H), 3.68 (t, J=6.1Hz, 2H), 3.01-2.83 (m, 2H), 2.03-1.86 (m, 2H), 0.94 (s, 9H), 0.08 (s,6H).

Method Q:3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propan-1-ol(xvii-a)

To a suspension of6-(3-(tert-butyldimethylsilyloxy)propyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine(0.35 g, 0.67 mmol) in MeOH (10 mL) was added 1-chloroethylchloroformate (7.2 μl, 0.067 mmol). The mixture was stirred overnight atroom temperature. Methanol was removed in vacuo. Sat. NaHCO₃ aqueous (10mL) and CH₂Cl₂ (10 mL) were added to the residue and stirred for awhile. The resultant solid was collected by filtration and dried to give0.25 g of3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propan-1-olas light yellow solid (91%). MS i/z=409 (M+1) (Method D) (retentiontime=1.71 min), ¹H NMR (300 MHz, DMSO) δ 10.01 (s, 1H), 9.51 (s, 1H),8.66 (m, 2H), 8.37 (s, 1H), 8.29-8.20 (m, 1H), 7.94-7.67 (m, 3H),7.63-7.43 (m, 2H), 4.60 (t, J=5.0 Hz, 1H), 3.56-3.35 (m, 2H), 2.94-2.69(m, 2H), 2.15-1.56 (m, 2H).

Method R:3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propylmethanesulfonate (xviii-a)

To a suspension of3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propan-1-ol(0.25 g, 0.61 mmol) and triethylamine (0.17 ml, 1.22 mmol) in CH₂Cl₂ (10mL) was added methanesulfonyl chloride (0.057 ml, 0.73 mmol). Themixture was stirred at room temperature for 1 h. Water (10 mL.) wasadded to the mixture and stirred for a while. The resultant precipitatewas collected by filtration and washed with CH₂Cl₂ and dried to give0.27 g of3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propylmethanesulfonate as pale yellow solid (91%), which was used withoutfurther purification.

Method G4:N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)propyl)-2-(pyridin-3-yl)quinazolin-4-aminedihydrochloride (xviv-a)

(This method is representative of method G4 and G5. These two methodscan be implemented in a similar way except for substitution of theappropriate solvent and temperature) A solution of3.-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propylmethanesulfonate (40 mg, 82 mmol) and 40% Me₂NH aqueous (1 mL) inmethanol (2 mL) was placed in a microwave reaction vial. The mixture washeated under microwave irradiation conditions at 150° C. for 30 minutesafter which the solvent was removed in vacuo. The crude product wasobtained, which was purified by column chromatography on basic silicagel (eluted with ethyl acetate/methanol 1:0→5:1). The HCl salt generatedby 4 M HCl in dioxane was crystallized from 2-propanol to give 10 mg ofN-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)propyl)-2-(pyridin-3-yl)quinazolin-4-aminedihydrochloride as pale brown powder (24%). LCMS m/z=436 (M+1) (MethodC) (retention time=1.68 min). ¹H NMR (300 MHz, DMSO) δ 10.59 (s, 1H),10.18 (s, 1H), 9.51 (s, 1H), 8.98-8.76 (m, 2H), 8.65 (s, 1H), 8.26 (dd,J=6.8, 2.6 Hz, 1H), 8.05-7.74 (m, 4H), 7.54 (t, J=9.1 Hz, 1H), 3.19-3.03(m, 2H), 2.97-2.83 (m, 2H), 2.78 (s, 3H), 2.77 (s, 3H), 2.16 (s, 2H).

N-(3-chloro-4-fluorophenyl)-6-(3-morpholinoprop-1-ynyl)-2-(pyridin-3-yl)quinazolin-4-amine (xx-a)

To a solution ofN-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amine(synthesized as described in Scheme 1 and 4, substituting5-iodo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and3-chloro-4-fluoroaniline for 2-aminobenzamide) (2.19 g, 4.6 mmol, 1eq.), Pd(PPh₃)₂Cl₂ (161 mg, 0.23 mmol, 0.05 eq.), CuI (87 mg, 0.46 mmol,0.1 eq.) in morpholine (15 mL) was added 3-bromoprop-1-yne (814 mg, 6.9mmol, 1.5 eq.) at 0° C. under Ar atmosphere, following a procedure fromTetrahedron, 2007, 63, 10671-10683. The mixture was stirred at 40° C.overnight. After cooling, the mixture was filtered and methanol (60 mL)was added to the filtrate to form a precipitate. The precipitate wascollected and re-crystallized from ethyl acetate twice to afford 1.60 gof xx-a as yellow solid (yield 74%). LCMS m/z=474.1 (M+1), 476.1 (M+3)(Method C) (retention time=1.97 min).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 8 substituting with appropriate nucleophile.

TABLE 3 Num- Salt Molecular ber Product type Mass ¹H-NMR 566

519.085 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.35 (s, 1H), 8.62-8.44(m, 3H), 8.11 (dd, J = 6.8, 2.6 Hz, 1H), 7.76-7.66 (m, 3H), 7.45-7.30(m, 2H), 4.48 (s, 2H), 0.75 (s, 9H), 0.00 (s, 6H). 567

523.117 1H NMR (300 MHz, CDCl3) δ 9.69 (dd, J = 2.2, 0.8 Hz, 1H),8.79-8.65 (m, 2H), 8.07 (dd, J = 6.5, 2.7 Hz, 1H), 7.94 (d, J = 8.5 Hz,1H), 7.76- 7.61 (m, 3H), 7.47-7.37 (m, 2H), 7.31-7.18 (m, 1H), 3.68 (t,J = 6.1 Hz, 2H), 3.01-2.83 (m, 2H), 2.03-1. 568

408.856 1H NMR (300 MHz, DMSO) δ 10.01 (s, 1H), 9.51 (s, 1H), 8.66 (m,2H), 8.37 (s, 1H), 8.29-8.20 (m, 1H), 7.94- 7.67 (m, 3H), 7.63-7.43 (m,2H), 4.60 (t, J = 5.0 Hz, 1H), 3.56-3.35 (m, 2H), 2.94-2.69 (m, 2H),2.15-1.56 (m, 2H). 569

2 HCl 508.846 1H NMR (300 MHz, DMSO) δ 10.59 (s, 1H), 10.18 (s, 1H),9.51 (s, 1H), 8.98-8.76 (m, 2H), 8.65 (s, 1H), 8.26 (dd, J = 6.8, 2.6Hz, 1H), 8.05-7.74 (m, 4H), 7.54 (t, J = 9.1 Hz, 1H), 3.19-3.03 (m, 2H),2.97-2.83 (m, 2H), 2.78 (s, 3H), 2.77 (s, 3H), 2. 570

409.841 1H NMR (300 MHz, CDCl3) δ 9.49 (d, J = 1.4 Hz, 1H), 8.73-8.51(m, 2H), 8.14 (s, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.81 (dd, J = 8.6, 1.9Hz, 1H), 7.51-7.13 (m, 4H), 3.77 (dd, J = 11.5, 6.2 Hz, 2H), 3.11-2.85(m, 2H), 2.16-1.93 (m, 2H), 1.44 (t, J = 5 571

2 HCl 550.882 1H NMR (300 MHz, DMSO) δ 10.83- 10.37 (m, 2H), 9.51 (s,1H), 8.97-8.74 (m, 2H), 8.62 (s, 1H), 8.27 (d, J = 4.2 Hz, 1H),8.05-7.72 (m, 4H), 7.54 (t, J = 9.0 Hz, 1H), 3.96 (d, J = 12.7 Hz, 2H),3.76 (t, J = 12.1 Hz, 2H), 3.47 (d, J = 12.0 Hz, 2H), 3.24 572

422.882 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.51 (s, 1H), 8.75-8.60(m, 2H), 8.37 (s, 1H), 8.26 (dd, J = 6.9, 2.6 Hz, 1H), 7.99-7.88 (m,1H), 7.88- 7.73 (m, 2H), 7.60-7.46 (m, 2H), 3.39 (dd, J = 8.4, 4.1 Hz,2H), 3.27 (s, 3H), 2.92-2.78 (m, 2H), 2.05 573

HCl 548.909 1H NMR (300 MHz, DMSO) δ 10.69 (s, 1H), 10.12 (s, 1H), 9.51(s, 1H), 9.02-8.30 (m, 2H), 8.69 (s, 1H), 8.27 (dd, J = 6.9, 2.7 Hz,1H), 8.08-7.78 (m, 4H), 7.54 (t, J = 9.1 Hz, 1H), 3.46 (d, J = 10.2 Hz,2H), 3.17-3.00 (m, 2H), 2.99-2.75 (m, 4H), 2.3 574

HCl 500.395 1H NMR (300 MHz, DMSO) δ 10.68 (s, 1H), 9.49 (s, 1H),9.12-8.99 (m, 1H), 8.94 (d, J = 3.9 Hz, 1H), 8.58 (d, J = 11.5 Hz, 1H),8.17 (dd, J = 6.7, 2.6 Hz, 1H), 8.07-7.82 (m, 5H), 7.55 (t, J = 9.1 Hz,1H), 3.43-3.29 (m, 2H), 3.08-2.65 (m, 5H), 2.09- 575

HCl 600.39 1H NMR (300 MHz, DMSO) δ 11.79 (s, 1H), 10.81 (s, 1H), 9.50(s, 1H), 8.98 (d, J = 8.2 Hz, 1H) 8.89 (d, J = 5.0 Hz, 1H), 8.75 (s,1H), 8.27 (d, J = 4.8 Hz, 1H), 8.10-7.79 (m, 4H), 7.53 (t, J = 9.1 Hz,1H), 5.18-3.09 (m, 10H), 3.01-2.69 (m, 5H), 2.37 576

473.93 1H NMR (300 MHz, DMSO) δ 10.17 (s, 1H), 9.52 (s, 1H), 8.70 (s,1H), 8.66 (d, J = 8.1 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.27 (dd, J =6.9, 2.6 Hz, 1H), 7.93 (s, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.61- 7.51 (m,2H), 3.67-3.61 (m, 6H), 2.61- 2.55 (m, 4H). 577

435.92 1H NMR (300 MHz, DMSO) δ 10.08 (s, 1H), 9.54 (s, 1H), 8.77-8.63(m, 2H), 8.52 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 6.8 Hz, 1H), 7.93 (s,1H), 7.79 (s, 1H), 7.64- 7.51 (m, 3H), 3.00 (t, J = 8.2 Hz, 2H), 2.87(t, J = 7.6 Hz, 2H), 2.72 (s, 6H), 2.14-1.99 ( 578

519.09 1H NMR (300 MHz, DMSO) δ 10.17 (s, 1H), 9.67-9.43 (m, 1H), 8.68(s, 2H), 8.55 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H), 7.89 (s, 2H), 7.68 (s,1H), 7.56 (d, J = 9.1 Hz, 2H), 4.64 (s, 2H), 0.92 (s, 9H), 0.18 (s, 6H).579

404.82 1H NMR (300 MHz, DMSO) δ 10.19 (s, 1H), 9.51 (s, 1H), 8.65 (d, J= 8.1 Hz, 2H), 8.64 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 7.85 (s, 2H),7.67-7.60 (m, 1H), 7.52 (d, J = 7.0 Hz, 2H), 5.48 (s, 1H), 4.39 (d, J =5.8 Hz, 2H). 580

477.96 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.51 (s, 1H), 8.73-8.61(m, 2H), 8.45 (d, J = 8.6 Hz, 1H), 8.28 (dd, J = 6.8, 2.5 Hz, 1H),7.97-7.86 (m, 1H), 7.71 (s, 1H), 7.60-7.47 (m, 3H), 3.63-3.51 (m, 4H),2.82 (t, J = 7.5 Hz, 2H), 2.42-2.25 (m, 6H), 581

523.12 1H NMR (300 MHz, CDCl3) δ 9.67 (d, J = 1.3 Hz, 1H), 8.76-8.66 (m,2H), 8.03 (dd, J = 6.5, 5.7 Hz, 1H), 7.82- 7.74 (m, 2H), 7.64 (ddd, J =8.9, 4.0, 2.7 Hz, 1H), 7.46 (s, 1H), 7.44-7.37 (m, 2H), 7.20 (t, J = 3.7Hz, 1H), 3.67 (t, J = 6.1 Hz, 2H), 2.95 582

408.86 1H NMR (300 MHz, CD3OD) δ 9.50 (d, J = 1.3 Hz, 1H), 8.77 (d, J =8.0 Hz. 1H), 8.62 (dd, J = 4.9, 1.6 Hz, 1H), 8.26 (d, J = 8.5 Hz, 1H),8.18 (dd, J = 6.7, 2.6 Hz, 1H), 7.83-7.71 (m, 2H), 7.61-7.47 (m, 2H),7.30 (t, J = 9.0 Hz, 1H), 3.65 (t, J = 6.4 Hz 583

494.03 1H NMR (300 MHz, CD3OD) δ 9.50- 9.46 (m, 1H), 8.77-8.70 (m, 1H),8.61 (dd, J = 4.9, 1.6 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.17 (dd, J =6.8, 2.6 Hz, 1H), 7.75 (ddd, J = 9.0, 4.2, 2.7 Hz, 1H), 7.70 (s, 1H),7.54 (ddd, J = 8.0, 4.9, 0.8 Hz, 1H), 7.46 (d 584

522 1H NMR (300 MHz, DMSO) δ 10.15 (s, 1H), 8.74-8.61 (m, 2H), 8.25 (d,J = 3.5 Hz, 1H), 7.96-7.80 (m, 4H), 7.59- 7.46 (m, 2H), 3.79 (s, 2H),3.18 (s, 4H), 3.06 (s, 4H). 585

526.06 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.52 (d, J = 2.0 Hz, 1H),8.72- 8.62 (m, 2H), 8.37 (s, 1H), 8.27 (dd, J = 6.9, 2.6 Hz, 1H),7.96-7.88 (m, 1H), 7.83 (d, J = 2.6 Hz, 2H), 7.61-7.50 (m, 2H), 3.10 (s,J = 17.4 Hz, 6H), 2.95-2.80 (m, 8H), 2.58- 586

HCl 494.82 1H NMR (300 MHz, DMSO) δ 10.49 (s, 1H), 9.50 (s, 1H),8.96-8.53 (m, 5H), 8.25 (dd, J = 6.9, 2.5 Hz, 1H), 8.05-7.73 (m, 4H),7.54 (t, J = 9.1 Hz, 1H), 3.02-2.78 (m, 4H), 2.64-2.37 (m, 3H),2.15-1.99 (m, 2H). 587

HCl 480.79 1H NMR (300 MHz, DMSO) δ 10.61 (s, 1H), 9.50 (s, 1H),9.00-8.78 (m, 2H), 8.66 (s, 1H), 8.25 (dd, J = 6.8, 2.6 Hz, 1H),8.13-7.75 (m, 7H), 7.54 (t, J = 9.1 Hz, 1H), 3.02-2.73 (m, 4H),2.14-1.94 (m, 2H). 588

431.89 1H NMR (300 MHz, DMSO) δ 10.18 (s, 1H), 8.65 (d, J = 6.6 Hz, 1H),8.56 (d, J = 8.7 Hz, 1H), 8.28 (dd, J = 6.9, 2.5 Hz, 1H), 8.01 (s, 1H),7.91 (dd, J = 7.0, 3.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.68-7.39 (m,3H), 4.07 (s, 2H), 2.67 (s, 6H). 589

435.92 1H NMR (300 MHz, DMSO) δ 10.06 (s, 1H), 9.53 (s, 1H), 8.76-8.62(m, 2H), 8.51 (d, J = 8.4 Hz, 1H), 8.28 (dd, J = 6.9, 2.5 Hz, 1H), 7.92(dd, J = 4.5, 1.8 Hz, 1H), 7.79 (s, 1H), 7.65-7.49 (m, 3H), 3.08-2.95(m, 2H), 2.86 (t, J = 7.6 Hz, 2H), 2.71 (s, J = 7.2 Hz, 6H), 2.05 (dt, J= 13.8, 7.1 Hz, 2H). 590

409.44 1H NMR (300 MHz, DMSO): δ 13.19 (s, 1H), 9.11 (s, 1H), 8.88 (s,1H), 8.53 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.94 (d, J = 10.6 Hz,4H), 7.78 (s, 1H), 7.25 (s, 1H), 4.44 (s, 2H), 3.37 (s, 3H). 591

413.47 ¹H-NMR Retention LCMS Purity Method for Number Solvent LCMS Time(Min) Protocol Percent Coupling 566 DMSO 519 (M + 1) 3.22 Method D 96Method O1 567 DMSO 523 (M + 1) 3.35 Method D 100 Methods O1, P 568 DMSO409 (M + 1) 1.71 Method D 100 Methods O1, P, Q 569 DMSO 436 (M + 1) 1.68Method C 100 Method G4 570 CDCl3 410 (M + 1) 1.95 Method D 100 MethodsO1, P, Q 571 DMSO 478 (M + 1) 2.01 Method C 100 Method G4 572 DMSO 423(M + 1) 2.09 Method D 100 Method G4 573 DMSO 476 (M + 1) 1.79 Method C100 Method G4 574 DMSO 464 (M + 1) 1.78 Method D 95 Method G4 followedby acylation with acetyl chloride/TE A/DCM, rt 575 DMSO 491 (M + 1) 1.76Method C 100 Method G4 576 DMSO 473.9 (M + 1) 2.2 Method C 100 Method O1577 DMSO 436.0 (M + 1) 1.68 Method C 100 Methods O1, P 578 DMSO 518.8(M + 1) 3.18 Method C 100 Method O1 579 DMSO 404.9 (M + 1) 2.05 Method C100 Methods O1, Q 580 DMSO 477.9 (M + 1) 1.99 Method C 100 Methods O1, P581 CDCl3 523.1 (M + 1) 3.35 Method C 100 Methods O1, P 582 CD3OD 409.0(M + 1) 1.99 Method C 100 Methods O1, P, Q 583 CD3OD 494.0 (M + 1) 2.29Method C 91 Method G4 584 DMSO 522.0 (M + 1) 2.18 Method C 100 Method O2585 DMSO 526.1 (M + 1) 2.11 Method C 91 Methods O2, P 586 DMSO 422(M + 1) 1.64 Method B (Ammonium formate) 100 Method O2 587 DMSO 408(M + 1) 1.60 Method B (Ammonium formate) 100 Method O2 588 DMSO 431.9(M + 1) Method C 99 Method O1 589 DMSO 436.0 (M + 1) Method C 99 MethodO1, P 590 DMSO 410.5 (M + 1) Method C 95 Method O1 591 DMSO 414.5(M + 1) Method C 95 Method O1, P

Method N1: Pd(APhos)₂Cl₂/K₃PO₄ or Cs₂CO₃/Boronic acid orester/Dioxane-H₂O, heatMethod N2: Pd(PPh₃)₂Cl₂/K₂CO₃/Boronic acid orester/DME-EtOH-H₂O/microwave, 120° C.Method N3: Pd(OAc)₂/Xphos/Cs₂CO₃/THF-H₂O, 80° C.Method N4: Pd(OAc)₂/Sphos/K₂CO₃/MeCN-H₂O, microwave, 120° C.Method N5: Pd(PPh₃)₄/K₃PO₄/Dioxane-H₂O, heatMethod N6: Pd(dppf)Cl₂—CH₂Cl₂/K₃PO₄/Dioxane-H₂O, heat

N-(3-chloro-4-fluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(pyridin-3-yl)quinazolin-4-amine(xxi-a)

A 2.0 dram reaction vial was charged with6-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine(synthesized as described in Scheme 1 and 4, substituting5-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol, 1.0equiv), 6-methoxypyridin-3-ylboronic acid (44.5 mg, 0.291 mmol, 1.25equiv), Pd(APhos)₂Cl₂ (6.6 mg, 0.0093 mmol, 4 mol %) and potassiumphosphate monohydrate (69 mg, 0.70 mmol, 3.0 equiv). The mixture wassuspended in dioxane/water (9:1, 4 mL), and the reaction was heated at90° C. for 14 h. The reaction mixture was cooled to room temperature,diluted with water (15 mL) and the resultant precipitate was collectedby filtration. The crude product was purified by stirring in methanolfor 30 min at 60° C. to give the desired product as a pale yellow solid(58 mg, 54%) LCMS m/z=458.1 (M+1) (Method C) (retention time=2.56 min).¹H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.53 (s, 1H), 8.82 (s, 1H), 8.70(dd, J=16.9, 5.4 Hz, 3H), 8.25 (d, J=8.6 Hz, 3H), 8.01-7.87 (m, 2H),7.57 (dd, J=11.2, 6.0 Hz, 2H), 7.03 (d, J=8.6 Hz, 1H), 3.94 (s, 3H).

N-(3-chloro-4-fluorophenyl)-7-(6-methoxypyridin-3-yl)-2-(pyridin-3-yl)quinazolin-4-amine(xxi-b)

A microwave vial was charged with7-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine(synthesized as described in Scheme 1 and 4, substituting4-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol),6-methoxypyridin-3-ylboronic acid (44.5 mg, 0.291 mmol, 1.25 equiv),Pd(PPh₃)₂Cl₂ (8.1 mg, 5 mol %) and potassium carbonate (160.1 mg, 1.16mmol, 5.0 equiv). The mixture was suspended in DME/water/ethanol (7:3:2,4 mL), and the reaction was heated under microwave irradiationconditions at 120° C. for 10 minutes. The crude reaction mixture wasdiluted with water (10 mL) and then filtered. The solid residue wasdissolved in methanol/THF (1:1, 5 mL) with heating and then filteredthrough Celite to remove the catalyst. The resulting filtrate wasconcentrated to afford the desired product as a tan solid (7.0 mg,6.5%). LCMS m/z=458.1 (M+1) (Method C) (retention time=2.51 min). ¹H NMR(300 MHz, DMSO) δ 10.12 (s, 1H), 9.55 (s, 1H), 8.76 (d, J=2.5 Hz, 1H),8.72-8.65 (m, 2H), 8.62 (d, J=8.6 Hz, 1H), 8.34-8.26 (m, 2H), 8.15 (d,J=1.6 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.97-7.88 (m, 1H), 7.61-7.49 (m,2H), 6.99 (d, J=8.7 Hz, 1H), 3.94 (s, 3H).

N-(3-chloro-4-fluorophenyl)-7-(piperidin-1-ylmethyl)-2-(pyridin-3-yl)quinazolin-4-amine(xxi-c)

A dry 15 mL sealed tube was charged with7-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine(synthesized as described in Scheme 1 and 4, substituting4-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol),potassium 1-trifluoroboratomethylpiperidine (52.5 mg, 0.256 mmol),cesium carbonate (227.5 mg, 0.698 mmol), Pd(OAc)₂ (1.6 mg, 3 mol %) andXPhos (6.7 mmol, 6 mol %) in THF/water (10:1, 3.3 mL). The reactionmixture was stirred at 80° C. for 16 hours. The reaction mixture wasfiltered through a pad of Celite and solvent was removed in vacuo. Thecrude product was purified by ISCO (silica, 12 g column, 97%dichloromethane-3% methanol-0.1% NH₄OH) to yield the desired compound asa yellow solid (23.3 mg, 22%). LCMS m/z=448.0 (M+1) (Method C)(retention time=1.95 min). ¹H NMR (300 MHz, CD₃OD) δ 9.40 (d, J=1.4 Hz,1H), 8.70-8.62 (m, 1H), 8.56 (dd, J=4.9, 1.6 Hz, 1H), 8.18-8.09 (m, 2H),7.69 (ddd, J=6.8, 4.1, 2.1 Hz, 2H), 7.54-7.45 (m, 2H), 7.23 (t, J=9.0Hz, 1H), 3.61 (s, 2H), 2.47 (s, 4H), 1.64 (dd, J=13.9, 8.9 Hz, 5H), 1.49(d, J=4.1 Hz, 2H).

N-(3-chloro-4-fluorophenyl)-6-(3-chlorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine(xxi-d)

A mixture ofN-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amine(1.0 g, 2.10 mmol), 3-chlorophenylboronic acid (0.49 g, 3.13 mmol),Pd(PPh₃)₄ (0.24 g, 0.210 mmol), K₃PO₄ (1.34 g, 6.31 mmol) in dioxane (20mL) and water (2.0 mL) was stirred under reflux for 2 h. Ethyl acetate(20 mL) was added to the cooled mixture and filtered. The filtered solidwas recrystallized from DMF and water to give the title compound (0.50g, 51.6%). ¹H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 9.54 (s, 1H), 8.87(s, 1H), 8.74-8.65 (m, 2H), 8.31-8.23 (m, 2H), 8.04-7.85 (m, 4H),7.64-7.49 (m, 4H).

2-(7-(3-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamidedihydrochloride (xxi-e)

A mixture of 2-(7-bromo-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide(0.40 g, 0.952 mmol), 3-fluorophenylboronic acid (0.20 g 1.43 mmol),Pd(dppf)₂Cl₂ (77 mg, 0.094 mmol), K₃PO₄ (606 mg, 2.85 mmol) in dioxane(8 mL) and water (2 mL) was refluxed under argon atmosphere for 4 h andcooled. Ethyl acetate (10 ml) was added to the mixture and a precipitateformed and was filtered. The filtered solid was recrystallized from DMFand water to give the title compound as free form. The solid as freeform was suspended in ethyl acetate (10 mL) and 4N HCl in ethyl acetate(0.71 mL) was added to the suspension. A precipitate formed and wassubjected to sonication for 20 min, filtered and dried to give the titlecompound (0.24 g, 49.6%). ¹H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 9.64(s, 1H), 9.21-9.08 (m, 1H), 9.07-8.89 (m, 2H), 8.51 (s, 1H), 8.38-8.26(m, 2H), 8.16 (d, J=8.5 Hz, 1H), 8.07-7.87 (m, 3H), 7.83-7.70 (m, 3H),7.62 (dd, J=14.2, 7.7 Hz, 1H), 7.40-7.22 (m, 2H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 11 substituting with appropriate boronicacid/ester or boronate salt, catalyst and solvent

TABLE 4 Num- Salt Molecular ber PRODUCT type Mass ¹H-NMR 592

2 HCl 536.401 ¹H NMR (300 MHz, DMSO) δ 11.34 (s, 1H), 10.53 (s, 1H),9.56 (s, 1H), 9.17- 8.95 (m, 2H), 8.89 (d, J = 4.5 Hz, 1H), 8.19 (d, J =8.8 Hz, 1H), 8.08-7.81 (m, 4H), 7.62-6.98 (m, 3H), 4.53 (s, 2H),4.05-3.74 (m, 4H), 3.48-3.07 (m, 4H). 593

HCl 515.406 ¹H NMR (300 MHz, DMSO) δ 10.40 (s, 1H), 9.51 (s, 1H),9.00-8.78 (m, 2H), 8.55 (s, 1H), 8.20 (d, J = 4.4 Hz, 1H), 8.03-7.75 (m,4H), 7.54 (t, J = 9.1 Hz, 1H), 4.68 (s, 2H), 3.83 (d, J = 11.2 Hz, 2H),3.44-3.18 (m, 4H), 1.98-1.78 (m, 1H), 1.62 (d, J 594

448.920 1H NMR (300 MHz, DMSO) δ 10.10 (s, 1H), 9.51 (s, 1H), 8.75-8.60(m, 2H), 8.47 (s, 1H), 8.32-8.19 (m, 1H), 7.97- 7.77 (m, 3H), 7.63-7.44(m, 2H), 4.62 (s, 2H), 4.16-3.97 (m, 1H), 1.88-1.42 (m, 8H). 595

457.89 ¹H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.53 (s, 1H), 8.82 (s,1H), 8.70 (dd, J = 16.9, 5.4 Hz, 3H), 8.25 (d, J = 8.6 Hz, 3H),8.01-7.87 (m, 2H), 7.57 (dd, J = 11.2, 6.0 Hz, 2H), 7.03 (d, J = 8.6 Hz,1H), 3.94 (s, 3H). 596

449.91 ¹H NMR (300 MHz, DMSO) δ 10.13 (s, 1H), 9.52 (s, 1H), 8.67 (d, J= 9.8 Hz, 2H), 8.47 (s, 1H), 8.34-8.20 (m, 1H), 8.02-7.84 (m, 3H), 7.54(t, J = 9.2 Hz, 2H), 3.64 (d, J = 17.6 Hz, 6H), 2.43 (s, 4H). 597

456.9 598

445.88 ¹H NMR (300 MHz, DMSO) δ 10.04 (s, 1H), 9.52 (s, 1H), 8.68 (t, J= 6.5 Hz, 2H), 8.51 (s, 1H), 8.22 (dd, J = 6.7, 2.4 Hz, 1H), 8.03-7.83(m, 3H), 7.54 (dd, J = 11.9, 6.6 Hz, 2H), 2.50 (s, 3H), 2.33 (s, 3H).599

427.86 ¹H NMR (300 MHz, DMSO) δ 10.10 (s, 1H), 9.51 (s, 1H), 9.13 (s,1H), 8.86 (s, 1H), 8.66 (s, 3H), 8.24 (s, 3H), 7.94 (d, J = 8.7 Hz, 2H),7.55 (dd, J = 16.7, 9.9 Hz, 3H). 600

430.86 ¹H NMR (300 MHz, DMSO) δ 9.98 (s, 1H), 9.51 (d, J = 1.6 Hz, 1H),8.66 (dd, J = 11.7, 2.2 Hz, 3H), 8.38- 8.20 (m, 2H), 8.20-8.02 (m, 2H),8.02-7.80 (m, 2H), 7.71- 7.42 (m, 2H), 3.93 (s, 3H). 601

449.91 ¹H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.52 (d, J = 1.3 Hz, 1H),8.77- 8.55 (m, 2H), 8.41 (s, 1H), 8.28 (dd, J = 6.9, 2.6 Hz, 1H),8.08-7.77 (m, 3H), 7.65-7.44 (m, 2H), 3.34 (s, 8H), 3.15- 2.90 (m, 5H),2.90-2.64 (m, 5H). 602

445.85 ¹H NMR (300 MHz, DMSO) δ 10.09 (s, 1H), 9.50 (s, 1H), 8.88-8.74(m, 2H), 8.66 (dd, J = 14.1, 5.5 Hz, 2H), 8.56- 8.42 (m, 1H), 8.23 (dd,J = 10.0, 5.7 Hz, 2H), 7.98-7.85 (m, 2H), 7.62-7.46 (m, 2H), 7.45-7.36(m, 1H). 603

512.97 ¹H NMR (300 MHz, DMSO) δ 10.05 (s, 1H), 9.51 (s, 1H), 8.70 (dd, J= 24.1, 7.0 Hz, 4H), 8.22 (dd, J = 14.3, 7.3 Hz, 2H), 8.10 (d, J = 7.9Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 7.4 Hz, 2H), 7.00 (d, J= 8.8 Hz, 1H), 3.74 (s, 4H), 3.55 (d, J = 4.7 604

456.9 ¹H NMR (300 MHz, DMSO) δ 10.16 (s, 1H), 9.53 (s, 1H), 8.81 (s,1H), 8.73- 8.60 (m, 2H), 8.30-8.20 (m, 2H), 7.99- 7.89 (m, 2H), 7.55(dd, J = 8.2, 4.7 Hz, 2H), 7.46 (t, J = 7.6 Hz, 3H), 7.10-6.96 (m, 1H),3.88 (s, 3H). 605

486.92 ¹H NMR (300 MHz, DMSO) δ 10.16 (s, 1H), 9.54 (s, 1H), 8.79 (d, J= 9.7 Hz, 1H), 8.71 (s, 2H), 8.26 (d, J = 8.7 Hz, 1H), 7.95 (dd, J =8.7, 3.7 Hz, 2H), 7.56 (dd, J = 11.7,6.4 Hz, 1H), 7.43 (d, J = 15.2 Hz,2H), 7.22-7.06 (m, 2H), 3.92 (s, 3H), 3.84 (s, 606

486.92 607

390.84 608

539.99 ¹H NMR (300 MHz, DMSO) δ 10.15 (s, 1H), 9.51 (s, 1H), 8.84 (s,1H), 8.66 (dd, J = 9.7, 6.5 Hz, 2H), 8.29-8.19 (m, 2H), 7.92 (ddd, J =8.9, 7.5, 4.6 Hz, 4H), 7.65-7.48 (m, 4H), 3.64 (s, 6H), 3.35 (s, 2H).609

526 610

471.91 ¹H NMR (300 MHz, DMSO) δ 10.03 (s, 1H), 9.56 (d, J = 2.1 Hz, 1H),8.77-8.66 (m, 3H), 8.64 (s, 1H), 8.24 (ddd, J = 8.7, 6.6, 2.6 Hz, 2H),8.13 (s, 1H), 7.96- 7.90 (m, 1H), 7.62-7.52 (m, 2H), 7.01 (d, J = 8.7Hz, 1H), 3.94 (s, 3H), 2.78 (s, 3H). 611

474.34 ¹H NMR (300 MHz, DMSO) δ 10.09 (s, 1H), 9.53 (s, 1H), 8.77 (s,1H), 8.67 (dd, J = 12.3, 4.1 Hz, 3H), 8.35 (d, J = 2.3 Hz, 1H),8.27-8.13 (m, 2H), 8.02-7.88 (m, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.55(dd, J = 7.7, 4.6 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 3. 612

442.88 613

465.91 ¹H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.54 (s, 1H), 8.75-8.63(m, 3H), 8.20 (dd, J = 8.2, 5.6 Hz, 2H), 8.09 (d, J = 8.5 Hz, 2H), 8.01(d, J = 8.5 Hz, 2H), 7.88 (s, 1H), 7.55 (d, J = 9.1 Hz, 2H), 2.76 (s,3H). 614

457.89 ¹H NMR (300 MHz, DMSO) δ 10.18 (s, 1H), 9.51 (s, 1H), 8.92 (s,1H), 8.67 (dd, J = 12.7, 5.8 Hz, 2H), 8.39-8.16 (m, 3H), 7.91(dd, J =14.8, 5.7 Hz, 2H), 7.65-7.45 (m, 3H), 7.35 (s, 1H), 3.94 (s, 3H). 615

514.93 ¹H NMR (300 MHz, DMSO) δ 10.19 (s, 1H), 9.52 (s, 1H), 8.86 (s,1H), 8.67 (dd, J = 10.1, 3.4 Hz, 2H), 8.28 (ddd, J = 9.4, 7.7, 2.1 Hz,2H), 8.06- 7.75 (m, 2H), 7.54 (dd, J = 9.0, 4.1 Hz, 4H), 3.99 (s, 3H),3.82 (s, 3H) 616

451.88 ¹H NMR (300 MHz, DMSO) δ 10.16 (s, 1H), 9.50 (s, 1H), 8.86 (s,1H), 8.66 (dd, J = 15.2, 6.9 Hz, 2H), 8.35- 8.16 (m, 2H), 8.15-7.82 (m,6H), 7.55 (dd, J = 11.1, 6.0 Hz, 2H). 617

436.47 618

421.45 619

449.91 ¹H NMR (300 MHz, DMSO) δ 10.06 (s, 1H), 9.52 (d, J = 1.3 Hz, 1H),8.73- 8.64 (m, 2H), 8.51 (d, J = 8.5 Hz, 1H), 8.27 (dd, J = 6.9, 2.6 Hz,1H), 7.96- 7.86 (m, 1H), 7.82 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.57(t, J = 3.9 Hz, 1H), 7.52 (t, J = 9.1 Hz, 1H), 3.69 (s, 2H), 3.62 (s,4H), 2.44 (s, 4H). 620

457.89 ¹H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.55 (s, 1H), 8.76 (d, J= 2.5 Hz, 1H), 8.72-8.65 (m, 2H), 8.62 (d, J = 8.6 Hz, 1H), 8.34-8.26(m, 2H), 8.15 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.97-7.88(m, 1H), 7.61-7.49 (m, 2H), 6.99 (d, J = 8.7 Hz, 1H), 3.94 (s, 3H). 621

462.95 ¹H NMR (300 MHz, CD₃OD) δ 9.40 (s, 1H), 8.66 (d, J = 8.0 Hz, 1H),8.56 (s, 1H), 8.19-8.09 (m, 2H), 7.74 (s, 1H), 7.72-7.65 (m, 1H),7.54-7.45 (m, 2H), 7.24 (t, J = 9.0 Hz, 1H), 3.68 (d, J = 8.0 Hz, 2H),2.75-2.41 (m, 8H), 2.30 (s, 3H). 622

433.91 623

435.92 624

430.865 ¹H NMR (300 MHz, DMSO) δ 10.01 (s, 1H), 9.52 (d, J = 1.3 Hz,1H), 8.72-8.60 (m, 2H), 8.49 (d, J = 8.6 Hz, 1H), 8.44 (s, 1H), 8.28(dd, J = 6.9, 2.6 Hz, 1H), 8.15 (s, 1H), 8.03 (d, J = 1.5 Hz, 1H),7.95-7.83 (m, 2H), 7.60-7.45 (m, 2H), 3.91 (s, 3H). 625

465.97 ¹H NMR (300 MHz, CD₃OD) δ 9.56-9.50 (m, 1H), 8.79 (dt, J = 8.1,1.6 Hz, 1H), 8.63 (dd, J = 4.9, 1.7 Hz, 1H), 8.30 (s, 1H), 8.19 (dd, J =6.7, 2.6 Hz, 1H), 7.91 (d, J = 1.1 Hz, 2H), 7.80 (ddd, J = 9.0, 4.2, 2.7Hz, 1H), 7.58 (dd, J = 8.0, 4.9 Hz, 1H), 7.33 (t, J = 9.0 Hz, 1H), 3.75(s, 2H), 2.84-2.66 (m, 8H). 626

491.94 ¹H NMR (300 MHz, DMSO) δ 10.00 (s, 1H), 9.52 (s, 1H), 8.73-8.63(m, 2H), 8.42 (s, 1H), 8.28 (dd, J = 6.8, 2.6 Hz, 1H), 7.92 (ddd, J =6.8, 4.2, 2.0 Hz, 1H), 7.85 (s, 2H), 7.60-7.50 (m, 2H), 3.56-3.43 (m,9H), 3.07 (t, J = 7.6 Hz, 2H), 2.79 (t, J = 7.7 Hz, 2H). 627

463.93 ¹H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.54 (s, 1H), 8.67 (d, J =5.3 Hz, 2H), 8.30-8.22 (m, 2H), 7.96-7.87 (m, 1H), 7.73 (s, 1H),7.60-7.46 (m, 2H), 3.60 (s, 6H), 2.71 (s, 3H), 2.41 (s, 4H). 628

419.43 ¹H NMR (300 MHz, DMSO) δ 9.41 (d, J = 1.4 Hz, 1H), 9.15 (d, J =1.7 Hz, 1H), 8.74- 8.64 (m, 3H), 8.55 (dt, J = 7.9, 1.8 Hz, 1H), 8.42(dd, J = 8.7, 2.0 Hz, 1H), 8.36-8.29 (m, 1H), 8.15 (d, J = 8.7 Hz, 1H),7.90 (dd, J = 7.8, 1.7 Hz, 1H), 7.61 (dd, J = 8.0, 4.8 Hz, 1H), 7.53(dd, J = 7.9, 4.8 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.5Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H). ¹H-NMR Retention LCMS Purity Methodfor Solvent LCMS Time (min) Protocol Percent Coupling DMSO 464 (M + 1)2.01 Method C 100 Method N3 DMSO 479 (M + 1) 2.08 Method D 97 Method N3DMSO 449 (M + 1) 2.62 Method D 92 Method N3 DMSO 458.2 (M + 1) 2.56Method C 100 Method N1 DMSO 449.9 (M + 1) 2.13 Method C 100 Method N3DMSO 456.0 (M + 1) 2.64 Method C 100 Method N1 DMSO 446 (M + 1) 2.35Method C 100 Method N1 DMSO 427.95 (M + 1) 2.25 Method C 100 Method N1DMSO 430.9 (M + 1) 2.17 Method C 100 Method N1 DMSO 449.9 (M + 1) 2.04Method C 100 Method N1 DMSO 445.9 (M + 1) 2.43 Method C 99 Method N1DMSO 512.9 (M + 1) 2.5 Method C 100 Method N1 DMSO 458.9 (M + 1) 2.65Method C 100 Method N1 DMSO 486.9 (M + 1) 2.48 Method C 100 Method N1DMSO 487.1 (M + 1) 2.58 Method C 100 Method N1 DMSO 390.9 (M + 1) 2.48Method C 100 Method N1 DMSO 539.9 (M + 1) 2.23 Method C 100 Method N1526.16 (M + 1) 2.55 Method C 94 Method N1 CDCl₃ 471.9 (M + 1) 2.93Method C 100 Method N1 DMSO 474.02 (M + 1) 2.72 Method C 100 Method N1DMSO 443.1 (M + 1) 2.37 Method C 100 Method N1 DMSO 466.1 (M + 1) 2.78Method C 100 Method N1 DMSO 458.1 (M + 1) 2.62 Method C 100 Method N1DMSO 515.1 (M + 1) 2.54 Method C 100 Method N1 DMSO 452.0 (M + 1) 2.61Method C 96 Method N1 437.2 (M + 1) 2.08 Method C 95 Method N1 422.2(M + 1) 1.8 Method C 100 Method N1 DMSO 449.9 (M + 1) 2.13 Method C 100Method N3 DMSO 458.1 (M + 1) 2.51 Method C 100 Method N2 CD₃OD 463.0(M + 1) 1.71 Method C 100 Method N3 434.0 (M + 1) 1.73 Method C 100Method N3 436.0 (M + 1) 1.84 Method C 100 Method N3 DMSO 431.0 (M + 1)2.12 Method C 100 Method N2 CD₃OD 466.0 (M + 1) 2.46 Method C 94 MethodN3 DMSO 491.9 (M + 1) 2 Method C 93 Method N1 DMSO 464.0 (M + 1) 2.52Method C 100 Method N3 DMSO 420.1 (M + 1) 2.12 Method C 99 Method N4Starting Starting Number Material 1 Material 2 629

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Salt Number Product type 629

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2 HCl 747

¹H NMR Purity Method of Number ¹H NMR Solvent Percent Coupling 629 ¹HNMR (400 MHz, DMSO) δ 10.20 (s, 1H), 9.54 (s, 1H), 8.87 (s, 1H),8.74-8.65 (m, 2H), 8.31- 8.23 (m, 2H), 8.04-7.85 (m, 4H), 7.64-7.49 (m,4H). DMSO >98 N5 630 ¹H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 9.54 (d, J= 1.4 Hz, 1H), 8.86 (s, 1H), 8.76- 8.64 (m, 2H), 8.26 (dd, J = 6.8, 2.3Hz, 2H), 8.03-7.89 (m, 4H), 7.70-7.52 (m, 4H). DMSO >98 N5 631 ¹H NMR(400 MHz, DMSO) δ 10.20 (s, 1H), 9.54 (d, J = 1.4 Hz, 1H), 8.86 (s, 1H),8.76- 8.64 (m, 2H), 8.26 (dd, J = 6.8, 2.3 Hz, 2H), 8.03-7.89 (m, 4H),7.70-7.52 (m, 4H). DMSO >98 N5 632 ¹H NMR (400 MHz, DMSO) δ 10.22-10.11(m, 1H), 9.54 (s, 1H), 8.86-8.77 (m, 1H), 8.74- 8.65 (m, 2H), 8.30-8.17(m, 2H), 8.01-7.90 (m, 2H), 7.74- 7.66 (m, 2H), 7.60-7.51 (m, 2H),7.51-7.42 (m, 1H), 7.28 (d, J = 7.5 Hz, 1H), 2.45 (s, 3H). DMSO >98 N5633 ¹H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 9.61-9.53 (m, 1H), 8.92 (s,1H), 8.73-8.67 (m, 2H), 8.43-8.24 (m, 3H), 8.14-7.89 (m, 3H), 7.84-7.76(m, 1H), 7.66-7.53 (m, 2H). DMSO >98 N5 634 ¹H NMR (400 MHz, DMSO) δ10.20 (s, 1H), 9.55 (d, J = 1.2 Hz, 1H), 8.89 (s, 1H), 8.75- 8.67 (m,2H), 8.35-8.22 (m, 2H), 8.00 (d, J = 8.7 Hz, 1H), 7.96- 7.90 (m, 1H),7.84-7.75 (m, 2H), 7.66-7.52 (m, 3H), 7.34-7.27 (m, 1H). DMSO >98 N5 635¹H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 9.54 (d, J = 1.2 Hz, 1H), 8.94(s, 1H), 8.77- 8.66 (m, 3H), 8.40-8.21 (m, 4H), 7.99 (d, J = 8.9 Hz,1H), 7.88 (t, J = 8.0 Hz, 2H), 7.61-7.50 (m, 2H). DMSO >98 N5 636 ¹H NMR(400 MHz, DMSO) δ 10.13 (s, 1H), 9.56 (s, 1H), 8.77-8.68 (m, 2H), 8.65(s, 1H), 8.27 (dd, J = 6.9, 2.6 Hz, 1H), 8.04-7.97 (m, 2H), 7.96-7.88(m, 1H), 7.70-7.43 (m, 6H). DMSO >98 N5 637 ¹H NMR (400 MHz, DMSO) δ10.10 (s, 1H), 9.56 (s, 1H), 8.76-8.68 (m, 2H), 8.63 (s, 1H), 8.28 (dd,J = 6.7, 2.7 Hz, 1H), 8.05 (dd, J = 8.7, 1.8 Hz, 1H), 8.00-7.90 (m, 2H),7.70- 7.43 (m, 4H), 7.21 (d, J = 8.1 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H),3.82 (s, 3H). DMSO >98 N5 638 ¹H NMR (400 MHz, DMSO) δ 10.16 (s, 1H),9.54 (s, 1H), 8.81 (s, 1H), 8.74-8.64 (m, 2H), 8.30- 8.17 (m, 2H),8.01-7.87 (m, 4H), 7.61-7.51 (m, 2H), 7.42 (t, J = 8.8 Hz, 2H). DMSO >98N5 639 1H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 9.57 (s, 1H), 8.80 (d, J= 1.8 Hz, 1H), 8.76-8.69 (m, 2H), 8.27 (dd, J = 6.9, 2.6 Hz, 1H), 8.14(dd, J = 8.6, 1.8 Hz, 1H), 8.10-8.02 (m, 2H), 7.97- 7.88 (m, 2H), 7.83(d, J = 6.8 Hz, 1H), 7.70 (td, J = 7.6, 1.2 Hz, 1H), 7.63-7.52 (m, 2H).DMSO >98 N5 640 ¹H NMR (400 MHz, DMSO) δ 10.12 (s, 1H), 9.55 (s, 1H),8.77- 8.66 (m, 2H), 8.62 (s, 1H), 8.25 (dd, J = 6.8, 2.3 Hz, 1H), 8.16(d, J = 8.3 Hz, 1H), 7.99-7.80 (m, 4H), 7.80-7.71 (m, 2H), 7.61- 7.49(m, 2H). DMSO >98 N5 641 1H NMR (400 MHz, DMSO) δ 9.57 (s, 1H),8.85-8.55 (m, 3H), 8.20-7.95 (m, 3H), 7.85-7.20 (m, 7H) DMSO >98 N5 642¹H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 9.55 (d, J = 1.2 Hz, 1H), 8.83(s, 1H), 8.74- 8.66 (m, 2H), 8.32-8.23 (m, 2H), 8.02-7.89 (m, 2H), 7.61-7.53 (m, 2H), 7.05 (d, J = 2.2 Hz, 2H), 6.62 (t, J = 2.1 Hz, 1H), 3.88(s, 6H). DMSO >98 N5 643 ¹H NMR (400 MHz, DMSO) δ 10.18 (s, 1H), 9.55(d, J = 2.0 Hz, 1H), 8.81 (d, J = 1.7 Hz, 1H), 8.74-8.65 (m, 2H), 8.31-8.20 (m, 2H), 8.04-7.88 (m, 2H), 7.65-7.53 (m, 2H), 7.42- 7.34 (m, 1H),7.23-7.09 (m, 2H), 6.83 (dd, J = 8.3, 1.9 Hz, 1H), 3.02 (s, 6H).DMSO >98 N5 644 1H NMR (400 MHz, DMSO) δ 10.14 (s, 1H), 9.55 (s, 1H),8.77- 8.68 (m, 2H), 8.65 (d, J = 1.5 Hz, 1H), 8.28 (dd, J = 6.9, 2.6 Hz,1H), 8.05 (dd, J = 8.6, 1.7 Hz, 1H), 8.01-7.90 (m, 2H), 7.60- 7.51 (m,2H), 7.29-7.21 (m, 1H), 7.18 (dd, J = 8.3, 1.6 Hz, 1H), 7.12 (dd, J =7.6, 1.6 Hz, 1H), 3.89 (s, 3H), 3.58 (s, 3H). DMSO >98 N5 645 1H NMR(400 MHz, DMSO) δ 10.09 (s, 1H), 9.56 (s, 1H), 8.74- 8.67 (m, 2H), 8.64(s, 1H), 8.28 (dd, J = 6.9, 2.6 Hz, 1H), 8.06 (dd, J = 8.6, 1.7 Hz, 1H),7.98- 7.89 (m, 2H), 7.62-7.51 (m, 2H), 7.14 (d, J = 9.0 Hz, 1H), 7.09(d, J = 3.1 Hz, 1H), 7.02 (dd, J = 8.9, 3.1 Hz, 1H), 3.81 (s, 3H), 3.76(s, 3H). DMSO >98 N5 646 1H NMR (400 MHz, DMSO) δ 9.99 (s, 1H), 9.56 (d,J = 0.9 Hz, 1H), 8.71 (dd, J = 7.1, 1.6 Hz, 2H), 8.46 (d, J = 1.5 Hz,1H), 8.29 (dd, J = 6.9, 2.6 Hz, 1H), 8.00-7.87 (m, 2H), 7.73 (dd, J =8.5, 1.7 Hz, 1H), 7.63-7.47 (m, 2H), 7.41 (t, J = 8.4 Hz, 1H), 6.84 (d,J = 8.5 Hz, 2H), 3.77-3.66 (m, 6H). DMSO >98 N5 647 ¹H NMR (400 MHz,DMSO) δ 10.06-9.96 (m, 1H), 9.52 (s, 1H), 8.75-8.62 (m, 3H), 8.40- 8.33(m, 1H), 8.28-8.22 (m, 1H), 8.22-8.14 (m, 1H), 7.97- 7.85 (m, 3H),7.64-7.49 (m, 2H), 7.16 (s, 1H). DMSO >98 N5 648 ¹H NMR (400 MHz, DMSO)δ 10.10 (s, 1H), 9.54 (s, 1H), 8.85 (s, 1H), 8.77-8.65 (m, 2H), 8.32 (d,J = 3.7 Hz, 1H), 8.26 (dd, J = 6.8, 2.6 Hz, 1H), 8.12 (s, 1H), 7.94 (d,J = 8.7 Hz, 2H), 7.86-7.76 (m, 2H), 7.64- 7.54 (m, 2H). DMSO >98 N5 6491H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 9.53 (s, 1H), 8.78 (s, 1H),8.71-8.64 (m, 2H), 8.26-8.19 (m, 2H), 7.95-7.90 (m, 2H), 7.77-7.69 (m,2H), 7.60-7.53 (m, 2H), 7.26 (t, J = 3.7 Hz, 1H). DMSO >98 N5 650 ¹H NMR(400 MHz, DMSO) δ 10.12 (s, 1H), 9.55 (d, J = 2.2 Hz, 1H), 8.75-8.67 (m,3H), 8.33-8.23 (m, 2H), 8.13 (dd, J = 8.7, 1.8 Hz, 1H), 8.00- 7.90 (m,3H), 7.63-7.51 (m, 2H), 7.22 (dd, J = 7.3, 5.0 Hz, 1H), 3.95 (s, 3H).DMSO >98 N5 651 ¹H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 9.53 (s, 1H),8.97 (s, 1H), 8.75 (d, J = 5.5 Hz, 2H), 8.73-8.64 (m, 2H), 8.38-8.30 (m,1H), 8.24 (d, J = 6.8 Hz, 1H), 8.05-7.97 (m, 1H), 7.97-7.88 (m, 3H),7.63-7.51 (m, 2H). DMSO >98 N5 652 1H NMR (400 MHz, DMSO) δ 10.05 (s,1H), 9.50 (s, 1H), 9.33 (s, 2H), 9.26 (s, 1H), 8.90 (s, 1H), 8.69 (d, J= 3.6 Hz, 1H), 8.64 (d, J = 8.0 Hz, 1H), 8.33 (d, J = 8.6 Hz, 1H), 8.22(dd, J = 6.7, 2.0 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.93-7.86 (m, 1H),7.61-7.48 (m, 2H). DMSO >98 N5 653 ¹H NMR (400 MHz, DMSO) δ 10.10 (s,1H), 9.55 (d, J = 1.2 Hz, 1H), 8.77-8.67 (m, 2H), 8.61 (s, 1H), 8.26(dd, J = 6.9, 2.6 Hz, 1H), 8.12 (dd, J = 8.7, 1.8 Hz, 1H), 8.01-7.89 (m,3H), 7.62-7.51 (m, 2H), 4.02 (s, 3H), 4.00 (s, 3H). DMSO >98 N5 654 ¹HNMR (400 MHz, DMSO) δ 10.09 (s, 1H), 9.56 (s, 1H), 8.77-8.68 (m, 2H),8.65 (d, J = 1.6 Hz, 1H), 8.30 (dd, J = 6.9, 2.6 Hz, 1H), 8.17 (dd, J =8.7, 1.7 Hz, 1H), 7.99-7.88 (m, 2H), 7.61-7.50 (m, 2H), 7.42-7.33 (m,2H), 7.21-7.08 (m, 2H), 2.53 (s, 6H). DMSO >98 N5 655 ¹H NMR (400 MHz,DMSO) δ 10.08 (s, 1H), 9.55 (s, 1H), 8.74-8.66 (m, 2H), 8.63 (s, 1H),8.26 (dd, J = 6.8, 2.5 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.97- 7.88 (m,3H), 7.62-7.51 (m, 2H), 6.61 (d, J = 3.1 Hz, 1H), 3.97 (s, 3H), 3.96 (s,3H). DMSO >98 N5 656 ¹H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 9.54 (d, J= 2.0 Hz, 1H), 8.91 (s, 1H), 8.76- 8.65 (m, 2H), 8.31 (d, J = 8.8 Hz,1H), 8.26 (dd, J = 6.8, 2.6 Hz, 1H), 8.15-7.89 (m, 7H), 7.61-7.52 (m,2H), 7.46 (s, 1H). DMSO >98 N5 657 ¹H NMR (400 MHz, DMSO) δ 10.21 (s,1H), 9.54 (d, J = 2.0 Hz, 1H), 8.91 (s, 1H), 8.76- 8.65 (m, 2H), 8.31.(d, J = 8.8 Hz, 1H), 8.26 (dd, J = 6.8, 2.6 Hz, 1H), 8.15-7.89 (m, 7H),7.61-7.52 (m, 2H), 7.46 (s, 1H). DMSO >98 N5 658 ¹H NMR (400 MHz, DMSO)δ 10.20 (s, 1H), 9.54 (s, 1H), 8.88 (s, 1H), 8.79-8.61 (m, 2H), 8.34-8.22 (m, 2H), 8.05-7.84 (m, 4H), 7.72 (t, J = 8.0 Hz, 1H), 7.65-7.53 (m,2H), 7.47 (d, J = 8.4 Hz, 1H). DMSO >98 N5 659 1H NMR (400 MHz, DMSO) δ10.06 (s, 1H), 9.53 (s, 1H), 8.75 (s, 1H), 8.75-8.66 (m, 3H), 8.28- 8.21(m, 1H), 8.20 (dd, J = 7.7, 1.8 Hz, 1H), 8.06 (dd, J = 8.9, 2.5 Hz, 1H),7.96-7.90 (m, 2H), 7.58-7.54 (m, 2H), 6.81 (d, J = 8.9 Hz, 1H), 3.11 (s,6H). DMSO >98 N5 660 ¹H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 9.54 (s,1H), 8.51 (s, 1H), 8.76 (s, 1H), 8.74-8.66 (m, 2H), 8.39 (d, J = 2.7 Hz,1H), 8.37-8.30 (m, 1H), 8.26 (dd, J = 6.8, 2.6 Hz, 1H), 8.03-7.97 (m,1H), 7.97-7.90 (m, 1H), 7.85 (d, J = 1.9 Hz, 1H), 7.62-7.52 (m, 2H),3.98 (s, 3H). DMSO >98 N5 661 ¹H NMR (400 MHz, DMSO) δ 10.06 (s, 1H),9.52 (d, J = 1.3 Hz, 1H), 8.76 (d, J = 19.6 Hz, 1H), 8.73-8.61 (m, 3H),8.29-8.16 (m, 3H), 7.99-7.87 (m, 2H), 7.61- 7.51 (m, 2H), 6.98 (d, J =8.6 Hz, 1H), 4.39 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H).DMSO >98 N5 662 ¹H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 9.53 (dd, J =2.1, 0.7 Hz, 1H), 8.75 (d, J = 1.9 Hz, 1H), 8.73-8.64 (m, 2H), 8.25 (dd,J = 6.9, 2.6 Hz, 1H), 8.19 (dd, J = 8.7, 1.9 Hz, 1H), 7.97-7.89 (m, 2H),7.61-7.50 (m, 3H), 7.41 (dd, J = 8.1, 1.9 Hz, 1H), 7.11 (d, J = 8.1 Hz,1H), 6.13 (s, 2H). DMSO >98 N5 663 ¹H NMR (400 MHz, DMSO) δ 10.19 (s,1H), 9.54 (s, 1H), 8.85 (s, 1H), 8.76-8.66 (m, 2H), 8.33- 8.22 (m, 2H),8.00-7.89 (m, 2H), 7.62-7.52 (m, 3H), 7.43 (s, 1H), 7.14 (s, 1H), 3.91(s, 3H). DMSO >98 N5 664 ¹H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 9.52(d, J = 1.3 Hz, 1H), 8.89-8.81 (m, 1H), 8.73-8.64 (m, 2H), 8.37-8.28 (m,1H), 8.28-8.21 (m, 1H), 8.01-7.86 (m, 2H), 7.81-7.69 (m, 2H), 7.60-7.51(m, 2H), 7.33 (s, 1H), 3.97 (s, 3H). DMSO >98 N5 665 1H NMR (400 MHz,DMSO) δ 10.1.9 (s, 1H), 9.53 (d, J = 1.9 Hz, 1H), 8.89 (s, 1H), 8.73-8.61 (m, 2H), 8.57 (d, J = 4.5 Hz, 1H), 8.34-8.18 (m, 2H), 8.09-7.86 (m,5H), 7.62-7.49 (m, 2H), 2.88-2.80 (m, 4H). DMSO >98 N5 666 ¹H NMR (400MHz, DMSO) δ 10.57 (s, 1H), 9.52 (d, J = 1.6 Hz, 1H), 9.21 (s, 2H),9.08- 9.02 (m, 1H), 9.02-8.96 (m, 1H), 8.89 (dd, J = 5.2, 1.5 Hz, 1H),8.39-8.30 (m, 1H), 8.25- 8.18 (m, 1H), 8.07-7.87 (m, 3H), 7.56 (t, J =9.1 Hz, 1H). DMSO >98 N5 667 ¹H NMR (400 MHz, DMSO) δ 10.78 (s, 1H),9.53 (s, 1H), 9.16- 9.02 (m, 2H), 8.99-8.88 (m, 1H), 8.66-8.55 (m, 1H),8.38 (d, J = 8.2 Hz, 1H), 8.20 (d, J = 5.0 Hz, 1H), 8.04 (dt, J = 27.3,13.6 Hz, 7H), 7.57 (t, J = 8.8 Hz, 1H), 2.84 (d, J = 3.8 Hz, 3H).DMSO >98 N5 668 ¹H NMR (400 MHz, DMSO) δ 10.49 (s, 1H), 9.53 (d, J = 1.5Hz, 1H), 8.99-8.83 (m, 3H), 8.34-8.25 (m, 1H), 8.21 (dd, J = 6.8, 2.6Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.98-7.91 (m, 1H), 7.86 (dd, J = 7.8,5.2 Hz, 1H), 7.78-7.70 (m, 2H), 7.57 (t, J = 9.1 Hz, 1H), 7.47 (t, J =7.6 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 2.45 (s, 6H). DMSO >98 N5 669 ¹HNMR (400 MHz, DMSO) δ 10.22 (s, 1H), 9.55 (d, J = 1.4 Hz, 1H), 8.81-8.70(m, 3H), 8.25 (dd, J = 6.8, 2.6 Hz, 1H), 8.13-8.05 (m, 1H), 7.99 (d, J =8.7 Hz, 1H), 7.97-7.89 (m, 1H), 7.64 (dd, J = 7.9, 4.9 Hz, 1H),7.61-7.49 (m, 2H), 7.37-7.26 (m, 2H), 2.41 (s, 3H). DMSO >98 N5 670 ¹HNMR (400 MHz, DMSO) δ 10.77 (s, 1H), 9.52 (d, J = 1.6 Hz, 1H), 9.09-8.95(m, 2H), 8.90 (dd, J = 5.2, 1.5 Hz, 1H), 8.41-8.29 (m, 1H), 8.23 (dd, J= 6.8, 2.6 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 8.01-7.88 (m, 2H), 7.56(t, J = 9.1 Hz, 1H), 7.50-7.38 (m, 2H), 7.32 (d, J = 8.2 Hz, 1H), 3.97(s, 3H), 2.23 (s, 3H). DMSO >98 N5 671 ¹H NMR (400 MHz, DMSO) δ 10.77(s, 1H), 9.52 (d, J = 1.6 Hz, 1H), 9.09-8.95 (m, 2H), 8.90 (dd, J = 5.2,1.5 Hz, 1H), 8.41-8.29 (m, 1H), 8.23 (dd, J = 6.8, 2.6 Hz, 1H), 8.05 (d,J = 8.7 Hz, 1H), 8.01-7.88 (m, 2H), 7.56 (t, J = 9.1 Hz, 1H), 7.50-7.38(m, 2H), 7.32 (d, J = 8.2 Hz, 1H), 3.97 (s, 3H), 2.23 (s, 3H). DMSO >98N5 672 ¹H NMR (400 MHz, DMSO) δ 10.67 (s, 1H), 9.47 (d, J = 1.6 Hz, 1H),9.04-8.94 (m, 2H), 8.89 (dd, J = 5.3, 1.5 Hz, 1H), 8.26 (dd, J = 8.8,1.9 Hz, 1H), 8.18 (dd, J = 6.8, 2.6 Hz, 1H), 8.09-8.00 (m, 1H),8.00-7.87 (m, 3H), 7.86-7.77 (m, 1H), 7.68-7.57 (m, 1H), 7.53 (t, J =9.1 Hz, 1H). DMSO >98 N5 673 ¹H NMR (400 MHz, DMSO) δ 10.82 (s, 1H),9.53 (s, 1H), 9.17- 9.04 (m, 1H), 9.04-8.93 (m, 2H), 8.34 (dd, J = 8.7,1.7 Hz, 1H), 8.18 (dd, J = 6.8, 2.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H),8.05- 7.89 (m, 2H), 7.57 (t, J = 9.0 Hz, 1H), 7.53-7.44 (m, 3H),7.09-6.98 (m, 1H), 4.82 (dt, J = 11.7, 5.9 Hz, 1H), 1.33 (d, J = 6.0 Hz,6H). DMSO >98 N5 674 ¹H NMR (400 MHz, DMSO) δ 10.60 (s, 1H), 9.50 (d, J= 1.7 Hz, 1H), 9.11-9.02 (m, 1H), 8.99-8.91 (m, 1H), 8.76 (d, J = 8.8Hz, 1H), 8.25 (d, J = 1.4 Hz, 1H), 8.19 (dd, J = 6.8, 2.6 Hz, 1H),8.10-7.92 (m, 4H), 7.82-7.72 (m, 1H), 7.65-7.56 (m, 1H), 7.52 (t, J =9.1 Hz, 1H). DMSO >98 N5 675 ¹H NMR (400 MHz, DMSO) δ 10.51 (s, 1H),9.51 (d, J = 1.7 Hz, 1H), 9.07-9.00 (m, 1H), 8.93 (dd, J = 5.3, 1.4 Hz,1H), 8.75 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 1.7 Hz, 1H), 8.21 (dd, J =6.8, 2.6 Hz, 1H), 8.10 (dd, J = 8.7, 1.9 Hz, 1H), 8.02-7.93 (m, 2H),7.74-7.65 (m, 2H), 7.52 (t, J = 9.1 Hz, 1H), 7.40- 7.31 (m, 1H).DMSO >98 N5 676 ¹H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 9.54 (d, J = 1.7Hz, 1H), 9.10 (d, J = 8.1 Hz, 1H), 8.95 (dd, J = 5.3, 1.4 Hz, 1H), 8.81(d, J = 8.7 Hz, 1H), 8.26-8.14 (m, 2H), 8.08-7.91 (m, 3H), 7.75-7.64 (m,1H), 7.51 (ddd, J = 14.7, 14.2, 6.9 Hz, 2H), 7.44-7.34 (m, 1H). DMSO >98N5 677 ¹H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 9.60-9.49 (m, 1H),9.37-9.31 (m, 1H), 8.99 (d, J = 8.3 Hz, 1H), 8.95-8.81 (m, 3H), 8.75 (d,J = 8.3 Hz, 1H), 8.40 (d, J = 1.7 Hz, 1H), 8.30-8.18 (m, 2H), 8.04-7.87(m, 3H), 7.56 (t, J = 9.1 Hz, 1H). DMSO >98 N5 678 ¹H NMR (400 MHz,DMSO) δ 10.42 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 9.38 (s, 2H), 9.30 (s,1H), 9.00-8.92 (m, 1H), 8.92- 8.86 (m, 1H), 8.76 (d, J = 8.7 Hz, 1H),8.34 (d, J = 1.7 Hz, 1H), 8.23 (dd, J = 6.8, 2.6 Hz, 1H), 8.15 (dd, J =8.6, 1.8 Hz, 1H), 7.99-7.85 (m, 2H), 7.52 (t, J = 9.1 Hz, 1H). DMSO >98N5 679 ¹H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 9.58-9.49 (m, 1H), 9.21(s, 2H), 9.09-8.98 (m, 1H), 8.92 (d, J = 3.8 Hz, 1H), 8.77 (d, J = 8.8Hz, 1H), 8.32 (d, J = 1.8 Hz, 1H), 8.27-8.20 (m, 1H), 8.15 (dd, J = 8.7,1.8 Hz, 1H), 8.03-7.89 (m, 2H), 7.55 (t, J = 9.1 Hz, 1H), 4.02 (s, 3H).DMSO >98 N5 680 ¹H NMR (400 MHz, DMSO) δ 10.09 (s, 1H), 9.56 (d, J = 1.3Hz, 1H), 8.75-8.67 (m, 2H), 8.60 (d, J = 8.7 Hz, 1H), 8.32 (dd, J = 6.9,2.6 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 8.03-7.87 (m, 4H), 7.60-7.50 (m,2H), 7.12 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H). DMSO >98 N5 681 ¹H NMR (400MHz, DMSO) δ 10.05 (s, 1H), 9.55-9.46 (m, 1H), 8.69-8.60 (m, 2H), 8.56(d, J = 8.7 Hz, 1H), 8.25 (dd, J = 6.9, 2.6 Hz, 1H), 8.10 (d, J = 1.8Hz, 1H), 7.96 (dd, J = 8.7, 1.9 Hz, 1H), 7.91-7.85 (m, 1H), 7.55-7.35(m, 5H), 7.03- 6.95 (m, 1H), 3.83 (s, 3H). DMSO >98 N5 682 ¹H NMR (400MHz, DMSO) δ 10.09 (s, 1H), 9.55 (d, J = 1.9 Hz, 1H), 8.74-8.67 (m, 2H),8.57 (d, J = 8.7 Hz, 1H), 8.32 (dd, J = 6.9, 2.6 Hz, 1H), 8.00- 7.91 (m,2H), 7.80 (dd, J = 8.6, 1.7 Hz, 1H), 7.60-7.41 (m, 4H), 7.21 (d, J = 7.8Hz, 1H), 7.12 (td, J = 7.4, 0.9 Hz, 1H), 3.84 (s, 3H). DMSO >98 N5 683¹H NMR (400 MHz, DMSO) δ 10.10 (s, 1H), 9.55 (s, 1H), 8.74- 8.65 (m,2H), 8.56 (d, J = 8.6 Hz, 1H), 8.35-8.26 (m, 1H), 7.99- 7.89 (m, 2H),7.81 (s, 1H), 7.70 (dd, J = 8.6, 1.6 Hz, 1H), 7.63- 7.47 (m, 6H), 7.40(s, 1H). DMSO >98 N5 684 ¹H NMR (400 MHz, DMSO) δ 10.16 (s, 1H),9.61-9.53 (m, 1H), 8.76-8.62 (m, 3H), 8.35- 8.28 (m, 1H), 8.24 (d, J =1.8 Hz, 1H), 8.16-7.99 (m, 6H), 7.99-7.92 (m, 1H), 7.63-7.51 (m, 2H),7.45 (s, 1H). DMSO >98 N5 685 ¹H NMR (400 MHz, DMSO) δ 10.21 (s, 1H),9.55 (d, J = 1.5 Hz, 1H), 8.78-8.62 (m, 3H), 8.31 (dd, J = 6.9, 2.6 Hz,1H), 8.15-8.00 (m, 2H), 8.00-7.80 (m, 5H), 7.74-7.65 (m, 1H), 7.64-7.51(m, 2H). DMSO >98 N5 686 ¹H NMR (400 MHz, DMSO) δ 10.18 (s, 1H),9.60-9.55 (m, 1H), 8.77-8.65 (m, 2H), 8.46 (s, 1H), 8.37-8.28 (m, 2H),8.17-8.10 (m, 1H), 7.99-7.93 (m, 2H), 7.81-7.72 (m, 2H), 7.62-7.50 (m,3H). DMSO >98 N5 687 ¹H NMR (400 MHz, DMSO) δ 10.18 (s, 1H), 9.56 (d, J= 2.2 Hz, 1H), 8.75-8.61 (m, 3H), 8.32 (dd, J = 6.8, 2.6 Hz, 1H), 8.07(s, 1H), 7.99-7.91 (m, 1H), 7.91-7.85 (m, 1H), 7.82-7.75 (m, 1H),7.61-7.50 (m, 3H), 7.47-7.36 (m, 2H). DMSO >98 N5 688 ¹H NMR (400 MHz,DMSO) δ 10.14 (s, 1H), 9.60-9.53 (m, 1H), 8.74-8.61 (m, 3H), 8.31 (dd, J= 6.9, 2.6 Hz, 1H), 8.20 (d, J = 1.8 Hz, 1H), 8.06 (dd, J = 8.7, 1.9 Hz,1H), 7.99-7.90 (m, 1H), 7.86-7.77 (m, 2H), 7.65-7.48 (m, 3H), 7.37-7.26(m, 1H). DMSO >98 N5 689 ¹H NMR (400 MHz, DMSO) δ 10.13 (s, 1H), 9.56(d, J = 1.5 Hz, 1H), 8.75-8.60 (m, 3H), 8.31 (dd, J = 6.9, 2.6 Hz, 1H),8.15 (d, J = 1.7 Hz, 1H), 8.07- 7.88 (m, 4H), 7.65-7.49 (m, 2H), 7.39(t, J = 8.8 Hz, 2H). DMSO >98 N5 690 ¹H NMR (400 MHz, DMSO) δ 10.14 (s,1H), 9.54 (d, J = 1.6 Hz, 1H), 8.76-8.60 (m, 3H), 8.34-8.25 (m, 1H),8.21 (d, J = 1.7 Hz, 1H), 8.13 (d, J = 8.4 Hz, 2H), 8.10-7.97 (m, 3H),7.97-7.87 (m, 1H), 7.62-7.45 (m, 2H). DMSO >98 N5 691 ¹H NMR (400 MHz,DMSO) δ 10.45 (s, 1H), 9.54 (d, J = 1.6 Hz, 1H), 8.99-8.91 (m, 1H),8.91-8.83 (m, 1H), 8.75 (d, J = 8.8 Hz, 1H), 8.42 (s, 1H), 8.31 (t, J =3.2 Hz, 1H), 8.29-8.22 (m, 2H), 8.13 (dd, J = 8.7, 1.8 Hz, 1H), 8.08 (d,J = 7.8 Hz, 1H), 8.03-7.92 (m, 2H), 7.86 (dd, J = 8.0, 5.2 Hz, 1H), 7.65(t, J = 7.7 Hz, 1H), 7.59-7.46 (m, 2H). DMSO >98 N5 692 ¹H NMR (400 MHz,DMSO) δ 10.38 (s, 1H), 9.56 (d, J = 1.5 Hz, 1H), 8.93 (d, J = 8.2 Hz,1H), 8.85 (dd, J = 5.1, 1.5 Hz, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.27 (dd,J = 6.8, 2.6 Hz, 1H), 8.21 (d, J = 1.7 Hz, 1H), 8.10 (dd, J = 8.7, 1.8Hz, 1H), 8.01- 7.90 (m, 3H), 7.83 (dd, J = 7.8, 5.0 Hz, 1H), 7.64-7.46(m, 4H). DMSO >98 N5 693 ¹H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 9.52(d, J = 1.5 Hz, 1H), 9.14 (d, J = 8.1 Hz, 1H), 9.00 (dd, J = 5.4, 1.2Hz, 1H), 8.91 (d, J = 8.8 Hz, 1H), 8.34 (d, J = 5.1 Hz, 1H), 8.20 (dd, J= 6.8, 2.6 Hz, 1H), 8.14- 8.04 (m, 2H), 8.04-7.89 (m, 2H), 7.75-7.48 (m,4H), 3.18 (s, 6H). DMSO >98 N5 694 ¹H NMR (400 MHz, DMSO) δ 10.99 (s,1H), 9.52 (d, J = 1.7 Hz, 1H), 9.08 (d, J = 8.0 Hz, 1H), 8.97 (dd, J =5.3, 1.4 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.33 (d, J = 2.3 Hz, 1H),8.18 (dd, J = 6.8, 2.6 Hz, 1H), 8.10 (dd, J = 8.8, 1.8 Hz, 1H),8.04-7.91 (m, 2H), 7.85 (d, J = 8.7 Hz, 2H), 7.56 (t, J = 9.1 Hz, 1H),7.09 (s, 2H), 3.05 (s, 6H). DMSO >98 N5 695 ¹H NMR (400 MHz, DMSO) δ10.67 (s, 1H), 9.53 (d, J = 1.7 Hz, 1H), 9.07 (d, J = 8.2 Hz, 1H), 8.95(dd, J = 5.3, 1.4 Hz, 1H), 8.78 (d, J = 8.7 Hz, 1H), 8.26 (s, 1H), 8.21(dd, J = 6.8, 2.6 Hz, 1H), 8.09 (dd, J = 8.7, 1.8 Hz, 1H), 8.04-7.92 (m,2H), 7.79-7.67 (m, 2H), 7.55 (t, J = 9.1 Hz, 1H), 7.46 (t, J = 7.6 Hz,1H), 7.32 (d, J = 7.5 Hz, 1H), 2.45 (s, 3H). DMSO >98 N5 696 ¹H NMR (400MHz, DMSO) δ 10.48 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 8.97 (d, J = 8.1Hz, 1H), 8.93-8.84 (m, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.30-8.16 (m, 2H),8.08 (dd, J = 8.7, 1.8 Hz, 1H), 8.01-7.78 (m, 4H), 7.55 (t, J = 9.1 Hz,1H), 7.39 (d, J = 7.9 Hz, 2H), 2.40 (s, 3H). DMSO >98 N5 697 ¹H NMR (400MHz, DMSO) δ 10.68 (s, 1H), 9.52 (s, 1H), 9.08 (d, J = 8.1 Hz, 1H), 8.95(d, J = 4.7 Hz, 1H), 8.82 (d, J = 8.7 Hz, 1H), 8.25-8.12 (m, 2H), 8.06-7.88 (m, 3H), 7.63-7.48 (m, 3H), 7.47-7.35 (m, 1H). DMSO >98 N5 698 ¹HNMR (400 MHz, DMSO) δ 10.47 (s, 1H), 9.53 (d, J = 1.6 Hz, 1H), 9.01-8.92(m, 1H), 8.87 (dd, J = 5.1, 1.4 Hz, 1H), 8.73 (d, J = 8.7 Hz, 1H), 8.24(dd, J = 6.8, 2.6 Hz, 1H), 8.09 (s, 1H), 7.99-7.78 (m, 4H), 7.59-7.42(m, 2H), 7.37-7.25 (m, 1H). DMSO >98 N5 699 ¹H NMR (400 MHz, DMSO) δ13.12 (s, 1H), 9.59 (s, 1H), 9.10 (d, J = 8.1 Hz, 1H), 9.00-8.86 (m,2H), 8.50 (s, 1H), 8.22- 8.07 (m, 2H), 8.03-7.86 (m, 4H), 7.72 (t, J =7.9 Hz, 1H), 7.28 (t, J = 7.1 Hz, 1H). DMSO >98 Scheme 4 synthesis usingmethod N6 coupling 700 ¹H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 9.64 (s,1H), 9.21-9.08 (m, 1H), 9.07-8.89 (m, 2H), 3.51 (s, 1H), 8.38- 8.26 (m,2H), 8.16 (d, J = 8.5 Hz, 1H), 8.07-7.87 (m, 3H), 7.83-7.70 (m, 3H),7.62 (dd, J = 14.2, 7.7 Hz, 1H), 7.40- 7.22 (m, 2H). DMSO >98 N6 701 ¹HNMR (400 MHz, DMSO) δ 13.17 (s, 1H), 9.65 (s, 1H), 9.13- 8.99 (m, 2H),8.89 (d, J = 5.1 Hz, 1H), 8.50 (s, 1H), 8.31 (d, J = 8.7 Hz, 1H), 8.21(d, J = 1.8 Hz 1H), 8.11 (dd, J = 3.6, 1.9 Hz, 1H), 8.05-7.84 (m, 5H),7.81-7.67 (m, 1H), 7.46-7.34 (m, 2H), 7.27 (dd, J = 11.8, 4.5 Hz, 1H).DMSO >98 N6 702 ¹H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 9.66 (d, J = 1.8Hz, 1H), 9.20 (d, J = 7.5 Hz, 1H), 9.04-8.89 (m, 2H), 8.50 (s, 1H), 8.35(d, J = 8.7 Hz, 1H), 8.17 (s, 1H), 8.11-7.86 (m, 4H), 7.86-7.68 (m, 2H),7.65-7.52 (m, 1H), 7.52-7.39 (m, 2H), 7.39-7.23 (m, 1H). DMSO >98 N6 703¹H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 9.62 (d, J = 1.6 Hz, 1H), 9.18(d, J = 8.2 Hz, 1H), 9.03-8.91 (m, 2H), 8.51 (s, 1H), 8.34-8.20 (m, 2H),8.16-7.86 (m, 5H), 7.84-7.68 (m, 2H), 7.68-7.54 (m, 1H), 7.35-7.19 (m,1H). DMSO >98 N6 704 ¹H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 9.61 (d, J= 1.8 Hz, 1H), 9.32-9.22 (m, 1H), 9.02 (dd, J = 5.5, 1.2 Hz, 1H), 8.88(d, J = 7.8 Hz, 1H), 8.75 (s, 1H), 8.53 (s, 1H), 8.28 (d, J = 8.7 Hz,1H), 8.16-8.07 (m, 2H), 8.01-7.88 (m, 3H), 7.85- 7.76 (m, 1H), 7.76-7.65(m, 1H), 7.54-7.42 (m, 1H), 7.37- 7.19 (m, 2H). DMSO >98 N6 705 ¹H NMR(400 MHz, DMSO) δ 13.20 (s, 1H), 9.63 (s, 1H), 9.26 (d, J = 8.1 Hz, 1H),9.01 (d, J = 5.0 Hz, 1H), 8.91 (d, J = 3.3 Hz, 1H), 8.52 (s, 1H), 8.33(d, J = 8.7 Hz, 1H), 8.21-8.06 (m, 2H), 8.06-7.87 (m, 3H), 7.72 (t, J =7.7 Hz, 1H), 7.66-7.52 (m, 2H), 7.49-7.35 (m, 1H), 7.29 (t, J = 7.5 Hz,1H). DMSO >98 N6 706 ¹H NMR (400 MHz, DMSO) δ 9.64 (d, J = 1.7 Hz, 1H),9.25 (d, J = 3.2 Hz, 1H), 9.05-8.89 (m, 2H), 8.67-8.45 (m, 1H), 8.34 (d,J = 8.7 Hz, 1H), 8.19 (s, 1H), 8.09 (dd, J = 8.0, 5.5 Hz, 1H), 8.04-7.88(m, 3H), 7.79-7.62 (m, 2H), 7.56-7.35 (m, 2H), 7.35-7.23 (m, 1H).DMSO >98 N6 707 ¹H NMR (400 MHz, DMSO) δ 13.18 (s, 1H), 9.62 (d, J = 1.6Hz, 1H), 9.16 (d, J = 8.1 Hz, 1H), 9.08-8.88 (m, 2H), 8.51 (s, 1H),8.37-8.23 (m, 2H), 8.19-8.09 (m, 1H), 8.09-7.88 (m, 3H), 7.83-7.63 (m,3H), 7.43-7.32 (m, 1H), 7.32-7.21 (m, 1H). DMSO >98 N6 708 ¹H NMR (400MHz, DMSO) δ 10.52 (s, 1H), 9.56 (d, J = 1.6 Hz, 1H), 9.04 (d, J = 7.8Hz, 1H), 8.92 (d, J = 4.8 Hz, 1H), 8.78 (d, J = 8.8 Hz, 1H), 8.24 (d, J= 1.7 Hz, 1H), 8.13-8.08 (m, 2H), 8.08-7.98 (m, 3H), 7.98-7.88 (m, 1H),7.63 (t, J = 8.2 Hz, 1H), 7.42 (t, J = 8.8 Hz, 2H), 7.28-7.15 (m, 1H).DMSO >98 N6/F5 followed by G1 709 ¹H NMR (400 MHz, DMSO) δ 10.60 (s,1H), 9.56 (s, 1H), 9.07 (d, J = 7.9 Hz, 1H), 8.93 (d, J = 4.3 Hz, 1H),8.77 (d, J = 8.7 Hz, 1H), 8.41 (s, 1H), 8.37-8.27 (m, 1H), 8.24 (d, J =1.7 Hz, 1H), 8.11 (dd, J = 8.7, 1.8 Hz, 1H), 8.08-7.94 (m, 3H),7.79-7.65 (m, 2H), 7.41 (t, J = 8.8 Hz, 2H). DMSO >98 N6/F5 followed byG1 710 1H NMR (DMSO-d6) ppm 3.81 (s, 3H), 3.88 (s, 3H), 7.11-7.71 (m,9H), 7.91 (d, 1H, J = 8.7 Hz), 8.23 (d, 1H, J = 8.7 Hz), 8.53-8.64 (m,2H), 8.87 (d, 1H, J = 1.5 Hz), 9.37 (d, 1H, J = 1.5 Hz), 9.83 (s, 1H)DMSO >98 N6/F5 followed by G1 711 1H NMR (DMSO-d6) ppm 3.89 (s, 3H),7.04 (d, 1H, J = 4.1 Hz), 7.48-7.57 (m, 5H), 7.98 (dd, 1H, J = 7.1, 1.7Hz), 8.26-8.29 (m, 3H), 8.27 (dd, 1H, J = 7.1, 8.7 Hz), 8.78-9.53 (m,3H), 9.54 (s, 1H), 10.37 (s, 1H) DMSO >98 N6/F5 followed by G1 712 1HNMR (DMSO-d6) ppm 3.89 (s, 3H), 7.05 (d, 1H, J = 4.1 Hz), 7.48-7.57 (m,4H), 7.88 (dd, 1H, J = 7.1, 1.7 Hz), 8.25-8.29 (m, 3H), 8.37 (dd, 1H, J= 7.1, 8.7 Hz), 8.78-9.53 (m, 3H), 9.54 (s, 1H), 10.37 (s, 1H) DMSO >98N6/F5 followed by G1 713 1H NMR (DMSO-d6) ppm 3.88 (s, 3H), 7.05-7.51(m, 9H), 7.95 (d, 1H, J = 8.7 Hz), 8.26 (d, 1H, J = 8.7 Hz), 8.54-8.88(m, 3H), 9.38 (s, 1H), 10.19 (s, 1H) DMSO >98 N6/F5 followed by G1 7141H NMR (DMSO-d6) ppm 3.89 (s, 3H), 7.04-7.06 (m, 2H), 7.46- 7.76 (m,8H), 7.95 (d, 2H, J = 8.6 Hz), 8.24 (d, 1H, J = 1.7 Hz), 8.69-8.87 (m,3H), 9.56 (s, 1H), 10.18 (s, 1H) DMSO >98 N6/F5 followed by G1 715 1HNMR (DMSO-d6) ppm 3.84 (s, 3H), 3.89 (s, 3H), 6.81-7.56 (m, 2H),7.40-7.70 (m, 7H), 7.95 (d, 1H, J = 8.5 Hz), 8.23 (d, 1H, J = 1.5 Hz),8.69-8.89 (m, 3H), 9.58 (s, 1H), 10.06 (s, 1H) DMSO >98 N6/F5 followedby G1 716 1H NMR (DMSO-d6) ppm 3.88 (s, 3H), 7.03-7.06 (m, 1H), 7.50-8.39 (m, 10H), 8.86-8.98 (m, 3H), 9.58 (s, 1H), 10.06 (s, 1H) DMSO >98N6/F5 followed by G1 717 1H NMR (DMSO-d6) ppm 3.89 (s, 3H), 7.02-7.07(m, 2H), 7.31 (s, 1H), 7.47-7.56 (m, 5H), 7.81- 8.26 (m, 4H), 8.26-8.90(m, 3H), 9.57 (s, 1H), 10.27 (s, 1H) DMSO >98 N6/F5 followed by G1 7181H NMR (DMSO-d6) ppm 3.87 (s, 3H), 7.03-7.50 (m, 8H), 7.98 (d, 1H, J =8.7 Hz), 8.30 (d, 1H, J = 8.7 Hz), 8.48-8.91 (m, 3H), 9.30 (s, 1H),10.19 (s, 1H) DMSO >98 N6/F5 followed by G1 719 1H NMR (DMSO-d6) ppm3.88 (s, 3H), 7.03-7.54 (m, 8H), 7.97 (d, 1H, J = 8.7 Hz), 8.28 (d, 1H,J = 8.7 Hz), 8.56-8.86 (m, 3H), 9.40 (s, 1H), 10.23 (s, 1H) DMSO >98N6/F5 followed by G1 720 1H NMR (DMSO-d6) ppm 3.88 (s, 3H), 7.03-7.52(m, 8H), 7.95 (d, 1H, J = 8.7 Hz), 8.26 (d, 1H, J = 8.7 Hz), 8.52-8.85(m, 3H), 9.38 (s, 1H), 10.17 (s, 1H) DMSO >98 N6/F5 followed by G1 7211H NMR (DMSO-d6) ppm 3.87 (s, 3H), 7.05-7.54 (m, 8H), 8.00 (d, 1H, J =8.7 Hz), 8.27 (d, 1H, J = 8.7 Hz), 8.55-8.87 (m, 3H), 9.38 (s, 1H),10.34 (s, 1H) DMSO >98 N6/F5 followed by G1 722 1H NMR (DMSO-d6) ppm3.89 (s, 3H), 7.05-7.53 (m, 7H), 7.93 (s, 1H), 7.96 (d, 1H, J = 8.7 Hz),8.16 (s, 1H), 8.26 (d, 1H, J = 8.7 Hz), 8.74-8.89 (m, 3H), 9.55 (s, 1H),10.27 (s, 1H) DMSO >98 N6/F5 followed by G1 723 1H NMR (DMSO-d6) ppm3.88 (s, 3H), 7.03-7.54 (m, 7H), 7.92 (s, 1H), 7.97 (d, 1H, J = 8.7 Hz),8.28 (d, 1H, J = 8.7 Hz), 8.56- 8.85 (m, 3H), 9.40 (s, 1H), 10.25 (s,1H) DMSO >98 N6/F5 followed by G1 724 1H NMR (DMSO-d6) ppm 3.88 (s, 3H),7.03-7.74 (m, 8H), 7.98 (d, 1H, J = 8.7 Hz), 8.27 (d, 1H, J = 8.7 Hz),8.52-8.87 (m, 3H), 9.32 (s, 1H), 10.22 (s, 1H) DMSO >98 N6/F5 followedby G1 725 1H NMR (DMSO-d6) ppm 3.89 (s, 3H), 7.05-7.71 (m, 8H), 7.99 (d,1H, J = 8.6 Hz), 8.30 (d, 1H, J = 8.7 Hz), 8.67-8.92 (m, 3H), 9.37 (s,1H), 10.52 (s, 1H) DMSO >98 N6/F5 followed by G1 726 1H NMR (DMSO-d6)ppm 3.89 (s, 3H), 7.03-7.71 (m, 9H), 7.99 (d, 1H, J = 8.7 Hz), 8.29 (d,1H, J = 8.7 Hz), 8.67-8.92 (m, 3H), 9.37 (s, 1H), 10.52 (s, 1H) DMSO >98N6/F5 followed by G1 727 1H NMR (DMSO-d6 at 70° C.) ppm 3.89 (s, 3H),7.02-7.52 (m, 8H), 7.90 (d, 1H, J = 8.5 Hz), 7.93 (s, 1H), 7.99 (d, 1H,J = 8.6 Hz), 8.22 (s, 1H), 8.74- 8.91 (m, 3H), 9.52 (s, 1H), 10.23 (s,1H) DMSO >98 N6/F5 followed by G1 728 ¹H NMR (DMSO-d₆) ppm 2.50 (s, 3H),3.89 (s, 3H), 7.06 (s, 1H), 7.49-7.85 (m, 9H), 8.01-8.96 (m, 4H), 9.58(s, 1H), 10.50 (s, 1H) DMSO >98 N6/F5 followed by G1 729 ¹H NMR(DMSO-d₆) ppm 3.89 (s, 3H), 7.04 (br s, 1H), 7.22 (s, 1H), 7.49-8.30 (m,9H), 8.77- 8.91 (m, 3H), 9.55 (s, 1H), 10.37 (s, 1H) DMSO >98 N6/F5followed by G1 730 ¹H NMR (DMSO-d₆) ppm 3.89 (s, 3H), 7.04 (s, 1H),7.49-8.32 (m, 9H), 8.91-9.04 (m, 3H), 9.54 (s, 1H), 10.63 (s, 1H)DMSO >98 N6/F5 followed by G1 731 ¹H NMR (DMSO-d₆) ppm 3.87 (s, 3H),7.03 (s, 1H), 7.44-8.25 (m, 9H), 8.71-8.84 (m, 3H), 9.52 (s, 1H), 10.23(s, 1H) DMSO >98 N6/F5 followed by G1 732 ¹H NMR (400 MHz, DMSO) δ 12.02(s, 1H), 10.53 (s, 1H), 9.49 (s, 1H), 9.02-8.72 (m, 3H), 8.30 (dd, J =8.7, 1.6 Hz, 1H), 8.05 (dd, J = 32.2, 5.3 Hz, 2H), 7.81-7.72 (m, 2H),7.49 (dd, J = 8.0, 5.4 Hz, 3H), 7.25 (t, J = 9.2 Hz, 1H), 7.11-6.98 (m,1H), 3.89 (s, 3H). DMSO >98 N6/F5 followed by G1 733 ¹H NMR (400 MHz,DMSO) δ 10.54 (s, 1H), 9.43 (s, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.64 (dd,J = 21.1, 5.9 Hz, 2H), 8.31 (dd, J = 8.7, 1.9 Hz, 1H), 8.01 (d, J = 8.7Hz, 1H), 7.59-7.45 (m, 4H), 7.42-7.30 (m, 3H), 7.09-6.98 (m, 1H), 3.89(s, 3H). DMSO >98 N6/F5 followed by G1 734 ¹H NMR (400 MHz, DMSO) δ13.18 (s, 1H), 10.57 (s, 1H), 9.48 (s, 1H), 8.98 (d, J = 1.3 Hz, 1H),8.78 (t, J = 7.1 Hz, 2H), 8.30 (dd, J = 8.7, 1.7 Hz, 1H), 8.18 (d, J =8.4 Hz, 2H), 8.01 (d, J = 8.7 Hz, 1H), 7.83 (dd, J = 8.9, 1.8 Hz, 1H),7.74- 7.62 (m, 2H), 7.56-7.43 (m, 2H), 7.09-7.01 (m, 1H), 3.90 (s, 3H).DMSO >98 N6/F5 followed by G1 735 ¹H NMR (400 MHz, DMSO) δ 11.16 (s,1H), 10.11 (s, 1H), 9.51 (d, J = 1.2 Hz, 1H), 8.91 (d, J = 1.7 Hz, 1H),8.71-8.58 (m, 2H), 8.23 (dd, J = 8.7, 1.9 Hz, 1H), 7.95 (dd, J = 23.9,5.2 Hz, 2H), 7.60-7.34 (m, 5H), 7.06-6.98 (m, 1H), 6.06 (s, 2H), 3.89(s, 3H). DMSO >98 N6/F5 followed by G1 736 ¹H NMR (400 MHz, DMSO) δ10.78 (s, 1H), 10.65 (s, 1H), 10.08 (s, 1H), 9.55 (d, J = 2.0 Hz, 1H),8.88 (d, J = 1.8 Hz, 1H), 8.76-8.66 (m, 2H), 8.24 (dd, J = 8.7, 1.9 Hz,1H), 7.94 (d, J78.7 Hz, 1H), 7.65 (d, J = 1.9 Hz, 1H), 7.58 (dd, J =7.7, 5.1 Hz, 1H), 7.49 (dt, J = 4.7, 3.1 Hz, 3H), 7.41 (dd, J = 8.4, 2.0Hz, 1H), 7.08-6.99 (m, 3H), 3.88 (s, 3H). DMSO >98 N6/F5 followed by G1737 ¹H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 9.40 (s, 1H), 8.86 (d, J =1.7 Hz, 1H), 8.64 (dd, J = 28.9, 5.8 Hz, 2H), 8.27 (dd, J = 8.7, 1.9 Hz,1H), 7.96 (d, J = 8.7 Hz, 1H), 7.87 (d, J = 2.6 Hz, 1H), 7.61-7.45 (m,5H), 7.38 (dd, J = 8.8, 2.6 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 7.09-6.98 (m, 1H), 3.89 (d, J = 2.9 Hz, 1H), 3.83 (s, 3H). DMSO >98 N6/F5followed by G1 738 ¹H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 9.56 (s, 1H),8.88 (d, J = 1.7 Hz, 1H), 8.75 (t, J = 7.2 Hz, 2H), 8.27 (dd, J = 8.6,1.4 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.84(dd, J = 8.2, 2.0 Hz, 1H), 7.63 (dd, J = 7.7, 4.9 Hz, 1H), 7.48 (dd, J =11.4, 4.0 Hz, 4H), 7.10-6.98 (m, 1H), 3.89 (s, 3H), 3.83 (s, 3H).DMSO >98 N6/F5 followed by G1 739 ¹H NMR (400 MHz, DMSO) δ 10.07 (s,1H), 9.55 (s, 1H), 8.85 (s, 1H), 8.70 (d, J = 5.5 Hz, 2H), 8.24 (dd, J =8.7, 1.5 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.99-7.83 (m, 2H), 7.60-7.40 (m, 4H), 7.30 (d, J = 9.0 Hz, 1H), 7.04 (dd, J = 7.1, 4.4 Hz, 1H),3.90 (s, 3H), 2.29 (s, 3H). DMSO >98 N6/F5 followed by G1 740 ¹H NMR(400 MHz, DMSO) δ 10.05 (s, 1H), 9.60 (s, 1H), 8.89 (d, J = 1.8 Hz, 1H),8.71 (dd, J = 12.8, 6.3 Hz, 2H), 8.24 (dd, J = 8.7, 1.9 Hz, 1H), 7.95(d, J = 8.7 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.61-7.45 (m, 5H), 7.44-7.37 (m, 1H), 7.24 (d, J = 8.0 Hz, 1H), 3.89 (s, 3H), 3.65 (s, 3H).DMSO >98 N6/F5 followed by G1 741 ¹H NMR (400 MHz, DMSO) δ 10.04 (s,1H), 9.60 (s, 1H), 8.89 (d, J = 1.7 Hz, 1H), 8.71 (dd, J = 12.7, 6.3 Hz,2H), 8.24 (dd, J = 8.7, 1.9 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.68 (d,J = 1.7 Hz, 1H), 7.59-7.45 (m, 4H), 7.44-7.37 (m, 1H), 7.25 (t, J = 6.7Hz, 1H), 7.07-6.98 (m, 1H), 3.89 (s, 6H), 2.19 (s, 3H). DMSO >98 N6/F5followed by G1 742 ¹H NMR (400 MHz, DMSO) δ 9.73 (s, 1H), 9.37 (s, 1H),8.86 (d, J = 1.6 Hz, 1H), 8.63 (d, J = 3.4 Hz, 1H), 8.54 (d, J = 8.0 Hz,1H), 8.23 (dd, J = 8.7, 1.8 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.55-7.42(m, 5H), 7.05- 6.98 (m, 1H), 6.77 (d, J = 2.6 Hz, 1H), 6.68 (dd, J =8.6, 2.6 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.79 (s, 3H). DMSO >98N6/F5 followed by G1 743 ¹H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 9.56(s, 1H), 8.84 (d, J = 1.7 Hz, 1H), 8.71 (d, J = 9.1 Hz, 1H), 8.27 (dd, J= 8.7, 1.8 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.86-7.77 (m, 2H),7.65-7.56 (m, 1H), 7.52-7.44 (m, 4H), 7.09-6.99 (m, 2H), 3.89 (s, 3H).DMSO >98 N6/F5 followed by G1 744 ¹H NMR (400 MHz, DMSO) δ 10.42 (s,1H), 9.55 (s, 1H), 8.87 (d, J = 26.7 Hz, 3H), 8.31 (dd, J = 8.7, 1.7 Hz,2H), 8.17 (d, J = 1.7 Hz, 2H), 8.02 (d, J = 8.7 Hz, 1H), 7.81 (s, 1H),7.54-7.39 (m, 3H), 7.11-6.98 (m, 1H), 3.89 (s, 3H). DMSO >98 N6/F5followed by G1 745 ¹H NMR (400 MHz, DMSO) δ 14.27 (s, 1H), 9.79 (s, 1H),9.32 (d, J = 8.4 Hz, 1H), 8.98 (d, J = 5.2 Hz, 1H), 8.34 (dd, J = 8.7,1.8 Hz, 1H), 8.29-8.19 (m, 2H), 8.07 (dd, J = 14.6, 8.3 Hz, 2H), 7.93(s, 1H), 7.64 (d, J = 5.9 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.39 (dd, J= 8.9, 4.9 Hz, 2H), 7.23 (d, J = 5.8 Hz, 1H), 7.08 (dd, J = 8.2, 1.8 Hz,1H), 3.86 (s, 3H). DMSO >98 N6/F5 followed by G1 746 ¹H NMR (400 MHz,DMSO) δ 11.10 (s, 1H), 9.36 (s, 1H), 9.11 (s, 1H), 9.00 (dd, J = 23.2,6.7 Hz, 2H), 8.41 (d, J = 9.1 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.05(dd, J = 7.9, 5.5 Hz, 1H), 7.80-7.65 (m, 2H), 7.59-7.44 (m, 3H),7.41-7.32 (m, 1H), 7.06 (d, J = 8.0 Hz, 1H), 3.90 (s, 3H). DMSO N6/F5followed by G1 747 ¹H NMR (400 MHz, DMSO) δ 12.92 (d, J = 17.9 Hz, 1H),9.64 (s, 1H), 9.09 (d, J = 7.9 Hz, 1H), 8.92 (d, J = 4.9 Hz, 1H), 8.52(d, J = 5.4 Hz, 1H), 8.38 (s, 1H), 8.30 (dd, J = 8.7, 1.7 Hz, 1H), 8.04(d, J = 8.7 Hz, 1H), 7.98- 7.84 (m, 3H), 7.50 (t, J = 7.9 Hz, 1H), 7.39(dd, J = 8.1, 5.0 Hz, 2H), 7.06 (dd, J = 8.2, 1.8 Hz, 2H), 3.89 (s, 3H).DMSO >98 N6/F5 followed by G1 Starting Starting Number Material 1Material 2 748

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2 HCl ¹H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 9.56 (s, 1H), 9.45 (s,2H), 9.29 (s, 1H), 9.22 (s, 1H), 9.13 (d, J = 7.8 Hz, 1H), 8.96 (d, J =4.3 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.16-8.08 (m, 2H), 8.07-7.99 (m,1H), 7.75 (s, 1H), 7.59 (dd, J = 19.3, 9.0 Hz, 1H). 749

¹H NMR (400 MHz, DMSO) δ 10.12 (s, 1H), 9.55 (d, J = 1.4 Hz, 1H),8.74-8.66 (m, 3H), 8.28 (d, J = 4.9 Hz, 1H), 8.17-8.08 (m, 2H),7.98-7.91 (m, 2H), 7.73 (d, J = 9.1 Hz, 1H), 7.61-7.51 (m, 2H), 7.22(dd, J = 7.3, 5.0 Hz, 1H), 3.95 (s, 3H). 750

2 HCl ¹H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 9.55 (d, J = 1.5 Hz, 1H),9.33 (s, 1H), 9.10-8.99 (m, 2H), 8.93 (d, J = 5.2 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.46 (dd, J = 8.8, 1.8 Hz, 1H), 8.33 (s, 1H), 8.18 (ddd, J= 13.0, 7.4, 2.4 Hz, 1H), 8.08 (d, J = 8.7 Hz, 1H), 8.01-7.93 (m, 1H),7.84 (d, J = 9.0 Hz, 1H), 7.57 (dd, J = 19.7, 9.1 Hz, 1H), 4.03 (s, 3H).751

HCl ¹H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 9.53 (d, J = 1.7 Hz, 1H),9.00 (dd, J = 14.9, 4.8 Hz, 2H), 8.90 (dd, J = 5.1, 1.4 Hz, 1H), 8.78(d, J = 2.1 Hz, 1H), 8.31 (dt, J = 8.7, 2.2 Hz, 2H), 8.11 (ddd, J =12.9, 7.5, 2.5 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.93 (dd, J = 8.0, 5.1Hz, 1H), 7.75 (dd, J = 6.0, 2.9 Hz, 1H), 7.63-7.51 (m, 1H), 7.03 (d, J =8.6 Hz, 1H), 3.94 (d, J = 8.4 Hz, 3H). 752

¹H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 9.52 (s, 1H), 9.14 (d, J = 5.6Hz, 2H), 8.84 (s, 1H), 8.68 (dd, J = 14.0, 6.4 Hz, 2H), 8.28 (dd, J =8.7, 1.7 Hz, 1H), 8.17-8.06 (m, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.70(d, J= 9.0 Hz, 1H), 7.62-7.50 (m, 2H), 4.02 (s, 3H). 753

¹H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 9.16(d, J = 1.9 Hz, 1H), 8.93 (d, J = 1.7 Hz, 1H), 8.74-8.60 (m, 3H),8.35-8.26 (m, 2H), 8.19-8.07 (m, 1H), 8.01 (d, J = 8.7 Hz, 1H),7.77-7.69 (m, 1H), 7.64-7.51 (m, 3H). 754

¹H NMR (400 MHz, DMSO) δ 10.12 (s, 1H), 9.53 (d, J = 1.4 Hz, 1H),8.79-8.62 (m, 3H), 8.24-8.06 (m, 2H), 7.94 (t, J = 7.7 Hz, 1H), 7.73(dd, J = 6.2, 2.9 Hz, 1H), 7.56 (ddd, J = 15.3, 10.1, 4.8 Hz, 3H), 7.41(dd, J = 8.1, 1.8 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.13 (s, 2H). 755

2 HCl ¹H NMR (400 MHz, DMSO) δ 11.36 (s, 1H), 9.73 (d, J = 1.7 Hz, 1H),9.52 (d, J = 1.8 Hz, 1H), 9.13-9.02 (m, 3H), 8.96 (dd, J = 5.4, 1.4 Hz,1H), 8.79 (d, J = 6.9 Hz, 2H), 8,56 (dd, J = 8.9, 1.9 Hz, 1H), 8.19(ddd, J = 13.0, 7.5, 2.5 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.02 (dd, J= 8.0, 5.4 Hz, 1H), 7.90 (dt, J = 9.0, 2.8 Hz,1H), 7.62-7.50 (m, 1H).756

¹H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 9.55 (d, J = 1.4 Hz, 1H), 8.86(d, J = 1.7 Hz, 1H), 8.69 (dd, J = 8.8, 2.9 Hz, 2H), 8.25 (dd, J = 8.7,1.8 Hz, 1H), 8.18-8.07 (m, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.92 (d, J =7.2 Hz, 2H), 7.78-7.68 (m, 1H), 7.62-7.53 (m, 4H), 7.47 (t, J = 7.4 Hz,1H). 757

2 HCl ¹H NMR (400 MHz, DMSO) δ 10.84 (s, 1H), 9.55 (s, 1H), 9.19-9.05(m, 2H), 8.95 (d, J = 4.1 Hz, 1H), 8.53 (s, 1H), 8.41 (dd, J = 8.7, 1.7Hz, 1H), 8.28 (s, 1H), 8.16-8.07 (m, 3H), 8.05-7.92 (m, 2H), 7.79(d, J =9.1 Hz, 1H), 7.70-7.46 (m, 3H). 758

2 HCl ¹H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 9.55 (d, J = 1.8 Hz, 1H),9.12 (d, J = 8.6 Hz, 2H), 8.96 (dd, J = 5.4, 1.4 Hz, 1H), 8.40 (dd, J =8.8, 1.8 Hz, 1H), 8.16-7.96 (m, 8H), 7.79-7.71 (m, 1H), 7.64-7.53 (m,1H), 7.47 (s, 1H). 759

HCl ¹H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 9.56 (s, 1H), 8.98-8.77 (m,3H), 8.23-8.02 (m, 4H), 7.99-7.65 (m, 5H), 7.56 (dd, J = 19.1, 9.4 Hz,1H). 760

2 HCl ¹H NMR (400 MHz, DMSO) δ 10.51 (s, 1H), 9.55 (d, J = 1.6 Hz, 1H),9.04 (d, J = 8.1 Hz, 1H), 8.95-8.84 (m, 2H), 8.21-8.02 (m, 3H), 7.93(dt, J = 10.6, 5.3 Hz, 1H), 7.77- 7.68 (m, 1H), 7.63-7.51 (m, 3H),7.49-7.38 (m, 1H). 761

2 HCl ¹H NMR (400 MHz, DMSO) δ 10.51 (s, 1H), 9.55 (d, J = 1.5 Hz, 1H),9.03 (d, J = 8.2 Hz, 1H), 8.91 (dd, J = 5.3, 1.5 Hz, 1H), 8.82 (s, 1H),8.16-8.00 (m, 3H), 7.94 (dd, J = 8.0, 5.2 Hz, 1H), 7.87-7.78 (m, 1H),7.75-7.66 (m, 1H), 7.61-7.44 (m, 2H), 7.39-7.28 (m, 1H). 762

HCl ¹H NMR (400 MHz, DMSO) δ 10.75 (s, 1H), 9.53 (d, J = 1.7 Hz, 1H),9.07 (dd, J = 23.2, 4.9 Hz, 2H), 8.95 (dd, J = 5.3, 1.4 Hz, 1H), 8.36(dd, J = 8.8, 1.9 Hz, 1H), 8.15-7.96 (m, 3H), 7.76 (dd, J = 9.0, 4.1 Hz,1H), 7.64-7.50 (m, 1H), 7.41 (dt, J = 12.9, 1.6 Hz, 2H), 6.99-6.90 (m,1H), 3.90 (s, 3H). 763

HCl ¹H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 9.55 (s, 1H), 9.05 (d, J =8.2 Hz, 1H), 8.92 (d, J = 4.6 Hz, 1H), 8.84 (s, 1H), 8.17-8.02 (m, 3H),7.96 (dd, J = 7.9, 5.4 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.56 (dd, J =19.6, 9.1 Hz, 1H), 7.39-7.21 (m, 3H), 3.89 (s, 3H). 764

HCl ¹H NMR (400 MHz, DMSO) δ 10.68 (s, 1H), 9.51 (d, J = 1.3 Hz, 1H),9.04 (d, J = 3.1 Hz, 1H), 8.97-8.87 (m, 2H), 8.51 (s, 1H), 8.32-8.22 (m,2H), 8.16-8.05 (m, 2H), 8.00- 7.90 (m, 2H), 7.80-7.73 (m, 1H), 7.65 (t,J = 7.8 Hz, 1H), 7.60-7.47 (m, 2H). 765

HCl ¹H NMR (400 MHz, DMSO) δ 10.43 (s, 1H), 9.46 (d, J = 1.3 Hz, 1H),9.01 (d, J = 8.1 Hz, 1H), 8.91 (d, 1H), 8.63 (s, 1H), 8.13-7.91 (m, 3H),7.73-7.66 (m, 1H), 7.59-7.49 (m, 2H), 7.44 (dd, J = 8.2, 1.8Hz, 1H),7.07 (d, J = 8.1 Hz, 1H), 6.12 (s, 2H). 766

¹H NMR (400 MHz, DMSO) δ 10.33 (s, 1H), 9.52 (s, 1H), 8.83 (s, 1H), 8.70(d, J = 6.3 Hz, 2H), 8.32 (d, J = 8.6 Hz, 2H), 8.13-8.03 (m, 1H), 7.70(d, J = 7.3 Hz, 1H), 7.58 (dd, J = 7.3, 5.7 Hz, 3H), 7.42 (s, 1H), 3.95(s, 3H). 767

2 HCl ¹H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 9.52-9.41 (m, 3H), 9.26(s, 1H), 9.11-9.02 (m, 2H), 8.96 (d, J = 5.4 Hz, 1H), 8.37 (d, J = 11.6Hz, 1H), 8.14-7.99 (m, 2H), 7.80-7.71 (m, 1H), 7.55 (d, J = 9.1 Hz, 1H).768

HCl ¹H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 9.51 (d, J = 1.6 Hz, 1H),9.07-9.00 (m, 1H), 8.91 (dd, J = 5.3, 1.5 Hz, 1H), 8.79 (s, 1H), 8.20(dd, J = 11.9, 1.6 Hz, 1H), 8.13- 8.03 (m, 1H), 8.00-7.91 (m, 3H),7.76-7.68 (m, 1H), 7.62-7.44 (m, 4H). 769

3 HCl ¹H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 9.64 (d, J = 1.7 Hz, 1H),9.47 (d, J = 1.5 Hz, 1H), 9.38 (s, 1H), 9.09 (t, J = 7.3 Hz, 2H),9.01-8.94 (m, 1H), 8.91-8.83 (m, 1H), 8.39 (dd, J = 11.6, 1.3 Hz, 1H),8.22-8.13 (m, 1H), 8.11-7.98 (m, 2H), 7.93-7.84 (m, 1H), 7.53 (dd, J =19.7, 9.2 Hz, 1H). 770

2 HCl ¹H NMR (400 MHz, DMSO) δ 10.69 (s, 1H), 9.55 (d, J = 1.7 Hz, 1H),9.12 (d, J = 8.2 Hz, 1H), 8.97 (dd, J = 5.4, 1.4 Hz, 1H), 8.81 (d, J =8.7 Hz, 1H), 8.30 (d, J = 1.3 Hz, 1H), 8.15-7.99 (m, 3H), 7.96-7.88 (m,2H), 7.81-7.72 (m, 1H), 7.63-7.47 (m, 4H). 771

3 HCl ¹H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 9.54-9.45 (m, 2H), 9.17(t, J = 8.6 Hz, 1H), 9.10-8.93 (m, 4H), 8.48 (d, J = 1.6 Hz, 1H),8.25-8.06 (m, 4H), 7.89-7.79 (m, 1H), 7.53 (dd, J = 19.6, 9.2 Hz, 1H).772

3 HCl ¹H NMR (400 MHz, DMSO) δ 10.67 (s, 1H), 9.54 (d, J = 1.7 Hz, 1H),9.40 (s, 2H), 9.31 (s, 1H), 9.20 (d, J = 8.2 Hz, 1H), 9.02 (d, J = 4.3Hz, 1H), 8.89 (d, J = 8.7 Hz, 1H), 8.43 (s, 1H), 8.22 (dd, J = 8.7, 1.9Hz, 1H), 8.17- 8.06 (m, 2H), 7.82-7.74 (m, 1H), 7.56 (dd, J = 19.7, 9.2Hz, 1H). 773

2 HCl ¹H NMR (400 MHz, DMSO) δ 10.81 (s, 1H), 9.56 (s, 1H), 9.11 (d, J =8.2 Hz, 1H), 8.94 (dd, J = 17.5, 6.7 Hz, 2H), 8.42 (d, J = 11.9 Hz, 2H),8.28 (s, 1H), 8.22-7.94 (m, 5H), 7.81 (d, J = 8.8 Hz, 1H), 7.71-7.45 (m,3H). 774

HCl ¹H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 9.54 (s, 1H), 8.95-8.78 (m,2H), 8.65 (d, J = 8.8 Hz, 1H), 8.19-8.09 (m, 2H), 8.02 (d, J = 8.7, 1H),7.85-7.69 (m, 2H), 7.62-7.37 (m, 3H), 7.09 (d, J = 7.0 Hz, 1H), 6.13 (s,2H). 775

2 HCl ¹H NMR (400 MHz, DMSO) δ 10.59 (s, 1H), 9.56 (d, J = 1.7 Hz, 1H),9.11 (d, J = 8.1 Hz, 1H), 9.01-8.88 (m, 1H), 8.79 (d, J = 8.7 Hz, 1H),8.18-8.06 (m, 2H), 8.05- 7.91 (m, 2H), 7.82-7.72 (m, 2H), 7.61-7.52 (m,2H), 7.48-7.37 (m, 2H). 776

2 HCl ¹H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 9.53 (d, J = 1.6 Hz, 1H),9.04 (dt, J = 8.1, 1.6 Hz, 1H), 8.91 (dd, J = 5.2, 1.4 Hz, 1H), 8.73 (d,J = 8.7 Hz, 1H), 8.24 (d, J = 1.8 Hz, 1H), 8.15-8.04 (m, 2H), 7.96 (dd,J = 8.0, 5.3 Hz, 1H), 7.84-7.70 (m, 2H), 7.65-7.48 (m, 2H), 7.39-7.25(m, 1H). 777

2 HCl ¹H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 9.55 (d, J = 1.7 Hz, 1H),9.12 (d, J = 8.1 Hz, 1H), 8.96 (dd, J = 5.3, 1.3 Hz, 1H), 8.78 (d, J =8.7 Hz, 1H), 8.25 (d, J = 1.7 Hz, 1H), 8.16-7.91 (m, 6H), 7.81-7.69 (m,1H), 7.56 (dd, J = 19.7, 9.1 Hz, 1H), 7.41 (t, J = 8.8 Hz, 1H). 778

2 HCl ¹H NMR (400 MHz, DMSO) δ 10.65 (s, 1H), 9.55 (d, J = 1.7 Hz, 1H),9.14 (d, J = 8.1 Hz, 1H), 8.97 (dd, J = 5.4, 1.3 Hz, 1H), 8.81 (d, J =8.7 Hz, 1H), 8.20-8.00 (m, 3H), 7.96-7.71 (m, 3H), 7.63-7.42 (m, 2H),7.38-7.25 (m, 1H). 779

HCl ¹H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 9.54 (d, J = 1.6 Hz, 1H),9.00 (d, J = 8.1 Hz, 1H), 8.90 (dd, J = 5.2, 1.4 Hz, 1H), 8.71 (d, J =8.7 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.17-8.01 (m, 3H), 7.93 (dd, J =8.0, 5.2 Hz, 1H), 7.84-7.71 (m, 2H), 7.69-7.49 (m, 2H). 780

2 HCl 1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 9.54 (d, J = 1.6 Hz, 1H),9.19 (d, J = 8.1 Hz, 1H), 9.06-8.96 (m, 1H), 8.87 (d, J = 8.7 Hz, 1H),8.22-8.04 (m, 3H), 7.93 (t, J = 10.1 Hz, 1H), 7.78 (dd, J = 6.1, 2.9 Hz,1H), 7.64- 7.49 (m, 3H), 7.47-7.35 (m, 1H). 781

2 HCl ¹H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 9.53 (d, J = 1.7 Hz, 1H),9.08 (d, J = 8.1 Hz, 1H), 8.94 (dd, J = 5.3, 1.3 Hz, 1H), 8.74 (d, J =8.8 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H), 8.17-7.95 (m, 3H), 7.80-7.55 (m,3H), 7.61-7.48 (m, 1H), 7.42-7.30 (m, 1H). 782

2 HCl ¹H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 9.63 (s, 1H), 9.20 (d, J =8.1 Hz, 1H), 8.97 (dd, J = 5.3, 1.3 Hz, 1H), 8.89 (d, J = 8.3 Hz, 1H),8.56 (d, J = 1.6 Hz, 1H), 8.46 (s, 1H), 8.31 (dd, J = 8.7, 1.8 Hz, 1H),8.13-7.92 (m, 4H), 7.90-7.83 (m, 2H), 7.77-7.70 (m, 1H), 7.59 (dd, J =10.4, 4.8 Hz, 2H), 7.53-7.46 (m, 2H), 7.34-7.25 (m, 1H). 783

2 HCl ¹H NMR (400 MHz, DMSO) δ 13.22 (s, 1H), 9.65 (s, 1H), 9.19 (d, J =8.1 Hz, 1H), 9.00-8.91 (m, 2H), 8.44 (d, J = 12.8 Hz, 2H), 8.18-7.89 (m,5H), 7.84-7.70 (m, 2H), 7.56-7.45 (m, 1H), 7.38-7.23 (m, 2H). 784

2 HCl ¹H NMR (400 MHz, DMSO) δ 13.15 (s, 1H), 9.65 (s, 1H), 9.38-9.27(m, 3H), 9.17 (d, J = 9.2 Hz, 1H), 8.92 (dd, J = 25.3, 6.7 Hz, 2H), 8.68(s, 1H), 8.45 (d, J = 8.9 Hz, 2H), 8.12 (d, J = 9.8 Hz, 1H), 8.04-7.92(m, 3H), 7.74 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 8.1 Hz, 1H). 785

2 HCl ¹H NMR (400 MHz, DMSO) δ 13.10 (s, 1H), 9.63 (s, 1H), 9.18 (d, J =8.0 Hz, 1H), 8.96 (dd, J = 5.3, 1.3 Hz, 1H), 8.87 (d, J = 8.1 Hz, 1H),8.46 (d, J = 21.1 Hz, 2H), 8.27 (dd, J = 8.7, 1.3 Hz, 1H), 8.09-7.89 (m,4H), 7.74 (t, J = 7.1 Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.38 (dd, J =8.1, 1.9 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H),6.12 (s, 2H). 786

2 HCl 1H NMR (DMSO-d6) ppm 9.79 (d, J = 1.56 Hz, 1H), 9.26 (brd, J = 7.2Hz, 1H), 9.00-8.90 (brm, 2H), 8.18 (d, J = 8.64 Hz, 1H), 8.11 (d, J =8.64 Hz, 1H), 8.01 (brt, J = 6.28 Hz, 1H), 7.86-7.80 (brm, 1H), 7.72 (d,J = 3.96 Hz, 1H), 7.53-7.46 (m, 2H), 7.37-7.32 (brm, 1H). The 1H of 2HCland NH— were not observed. 787

1H NMR (DMSO-d6) ppm 12.63 (brs, 1H), 9.80 (d, J = 1.64 Hz, 1H),9.05-8.91 (brm, 2H), 8.76 (brd, J = 4.6 Hz, 1H), 8.10 (brd, J = 8.64 Hz,1H), 8.02 (d, J = 8.64 Hz, 1H), 7.86-7.80 (brm, 1H), 7.66-7.62 (brm,1H), 7.51-7.45 (brm, 1H), 7.34-7.30 (brm, 1H), 6.94 (brs, 1H), 2.35(brs, 3H). 788

1H NMR (300 MHz, CD3OD) δ 9.40 (s, 1H), 8.65 (s, J = 8.0 Hz, 1H), 8.56(d, J = 3.2 Hz, 1H), 8.18-8.08 (m, 2H), 7.76- 7.65 (m, 2H), 7.54-7.44(m, 2H), 7.23 (t, J = 9.0 Hz, 1H), 3.66 (s, J = 8.0 Hz, 2H), 2.55 (s, J= 20.6 Hz, 8H), 2.30 (s, 3H). 789

790

791

¹H-NMR (400 MHz, DMSO-d₆): δ 12.20 (s, 1H), 9.64 (s, 1H), 9.58 (s, 1H),8.73 (d, J = 5.5 Hz, 2H), 8.60 (s, 1H), 8.53 (dd, J = 7.2, 1.5 Hz, 1H),8.28-8.25 (m, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.61-7.58 (m, 1H), 7.50 (t,J = 4.5 Hz, 3H), 7.30 (d, J = 5.8 Hz, 1H), 7.06 (dd, J = 7.4, 4.1 Hz,1H), 6.49 (t, J = 6.9 Hz, 1H), 3.91 (s, 3H). 792

HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 13.42 (s, 1H), 8.99 (d, J = 8.0 Hz,1H), 8.64 (td, J = 7.6, 2.0 Hz, 1H), 8.51 (s, 1H), 8.44 (d, J = 4.4 Hz,1H), 8.01-7.95 (m, 3H), 7.68-7.58 (m, 4H), 7.24 (t, J = 7.8 Hz, 1H),4.26 (q, J = 2.8 Hz, 2H), 1.47 (t, J = 2.8 Hz, 3H). 793

HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 10.31 (s, 1H), 9.13 (d, J = 2.0 Hz,1H), 8.83 (td, J = 8.4, 2.4 Hz, 1H), 8.09 (d, J = 1.2 Hz, 2H), 7.93 (d,J = 8.4 Hz, 2H), 7.66-7.60 (m, 2H), 7.36 (dd, J = 8.8, 2.4 Hz, 1H), 7.22(d, J = 8.0 Hz, 1H), 4.28 (q, J = 6.8 Hz, 2H), 1.47 (t, J = 6.8 Hz, 3H).794

2HCl 795

3HCl 1H-NMR (300 MHz, DMSO): δ 13.10 (s, 1H), 9.61 (s, 1H), 9.12 (d, J =9.8 Hz, 1H), 8.93 (s, 1H), 8.83 (d, J = 15.2 Hz, 2H), 8.66 (s, 1H),8.58-8.36 (m, 3H), 8.08 (d, J = 11.6 Hz, 2H),7.96 (d, J = 9.2 Hz, 3H),7.73 (s, 1H), 7.29 (t, J = 8.7 Hz, 1H), 4.02 (s, 3H). 796

3HCl 1H-NMR (300 MHz, DMSO): δ 12.79 (s, 1H), 9.54 (d, J = 1.6 Hz, 1H),9.18 (d, J = 8.2 Hz, 1H), 9.08 (d, J = 6.7 Hz, 2H), 9.05-8.96 (m, 2H),8.63-8.46 (m, 4H), 8.39 (s, 1H), 8.08 (dd, J = 11.6, 8.5 Hz, 2H), 7.92(d, J = 6.7 Hz, 1H), 7.77 (s, 1H), 7.68 (t, J = 7.1 Hz, 1H), 7.32 (t, J= 7.2 Hz, 1H). 797

3HCl 1H-NMR (300 MHz, DMSO): δ 12.81 (s, 1H), 9.54 (s, 1H), 9.45 (s,1H), 9.23 (d, J = 8.2 Hz, 1H), 9.08-8.93 (m, 3H), 8.83 (s, 1H), 8.52 (d,J = 8.2 Hz, 1H), 8.47-8.34 (m, 2H), 8.14 (ddd, J = 12.9, 8.1, 4.9 Hz,3H), 7.92 (d, J = 6.6 Hz, 1H), 7.79 (s, 1H), 7.68 (t, J = 7.2 Hz, 1H),7.32 (t, J = 7.2 Hz, 1H). 798

2HCl 1H-NMR (300 MHz, DMSO): δ 13.20 (s, 1H), 9.62 (s, 1H), 9.13 (d, J =8.1 Hz, 1H), 8.94 (d, J = 3.5 Hz, 2H), 8.55 (s, 1H), 8.48 (s, 1H), 8.31(d, J = 8.7 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.96 (s, 3H), 7.74 (s,1H), 7.55-7.40 (m, 3H), 7.29 (s, 1H), 7.06 (d, J = 7.4 Hz, 1H), 3.90 (s,3H). 799

1H-NMR (300 MHz, DMSO): δ 13.13 (s, 1H), 9.60 (d, J = 1.4 Hz, 1H), 9.12(d, J = 7.8 Hz, 1H), 8.73 (dd, J = 9.7, 6.4 Hz, 2H), 8.52 (s, 1H), 8.35(s, 1H), 8.28 (s, 1H), 8.14 (d, J = 8.7 Hz, 1H), 8.08-7.88 (m, 4H), 7.76(d, J = 7.2 Hz, 1H), 7.59 (dd, J = 7.4, 4.8 Hz, 1H), 7.23 (t, J = 7.1Hz, 1H), 3.94 (s, 3H). 800

¹H NMR (400 MHz, DMSO) δ 10.08 (s, 1H), 9.59-9.49 (m, 1H), 8.79-8.63 (m,3H), 8.55 (d, J = 2.1 Hz, 1H), 8.27 (dd, J = 6.9, 2.6 Hz, 1H), 8.18 (dd,J = 8.7, 1.9 Hz, 1H), 8.02- 7.90 (m, 3H), 7.63-7.51 (m, 2H), 6.62 (d, J= 8.6 Hz, 1H), 6.24 (s, 2H). 801

1H NMR (DMSO-d6) ppm 9.78 (brs, 1H), 9.20-8.80 (br, 3H), 8.14 (brd, J =8.64 Hz, 1H), 8.04 (d, J = 8.64 Hz, 1H), 7.83 brm, 2H), 7.52-7.47 (m,1H), 7.35-7.31 (m, 1H), 7.00 (brs, 1H), 2.36 (brs, 3H), 2.30 (brs, 3H).The 1H of MsOH and NH were not observed. ¹H NMR Purity Method LCMSNumber Solvent percent of Coupling LCMS Method 748 DMSO >98 Method N6749 DMSO >98 Method N6 750 DMSO >98 Method N6 751 DMSO >98 Method N6 752DMSO >98 Method N6 753 DMSO >98 Method N6 754 DMSO >98 Method N6 755DMSO >98 Method N6 756 DMSO >98 Method N6 757 DMSO >98 Method N6 758DMSO >98 Method N6 759 DMSO >98 Method N6 760 DMSO >98 Method N6 761DMSO >98 Method N6 762 DMSO >98 Method N6 763 DMSO >98 Method N6 764DMSO >98 Method N6 765 DMSO >98 Method N6 766 DMSO >98 Method N6 767DMSO >98 Method N6 768 DMSO >98 Method N6 769 DMSO >98 Method N6 770DMSO >98 Method N6 771 DMSO >98 Method N6 772 DMSO >98 Method N6 773DMSO >98 Method N6 774 DMSO >98 Method N6 775 DMSO >98 Method N6 776DMSO >98 Method N6 777 DMSO >98 Method N6 778 DMSO >98 Method N6 779DMSO >98 Method N6 780 DMSO >98 Method N6 781 DMSO >98 Method N6 782DMSO >98 Method N6 783 DMSO >98 Method N6 784 DMSO >98 Method N6 785DMSO >98 Method N6 786 DMSO >98 N6 using Na₂CO₃ instead of K₃PO₄ 787DMSO >98 N6 using Na₂CO₃ instead of K₃PO₄ 788 CD3OD   99 Method N3 463.0(M + 1) Method C 789   99 Method N3 434.0 (M + 1) Method C 790   99Method N3 436.0 (M + 1) Method C 791 DMSO   95 Method N1 422.2 (M + 1)Method B (NH4HCO3) 792 DMSO   95 Method N1 404.0 (M + 1) Method B(NH4HCO3) 793 DMSO   95 Method N1 445.0 (M + 1) Method B (NH4HCO3) 794DMSO   95 Method N1 382.5 (M + 1) Method C 795 DMSO   95 Method N1 449.4(M + 1) Method C 796 DMSO   95 Method N1 419.1 (M + 1) Method C 797 DMSO  95 Method N1 419.1 (M + 1) Method C 798 DMSO   95 Method N1 448.1(M + 1) Method C 799 DMSO   95 Method N1 422.2 (M + 1) Method C 800DMSO >98 N5 801 DMSO >98 N6 using Na₂CO₃ instead of K₃PO₄ Salt MolecularNumber PRODUCT type Mass 802

494.87 803

458.89 804

427.86 805

426.87 806

456.9 807

456.9 ¹H-NMR LCMS Purity Method for Number ¹H-NMR Solvent LCMS Protocolpercent Coupling 802 ¹H-NMR (400 MHz, DMSO-d₆): δ10.18 (s, 1H), 9.21 (d,J = 1.8 Hz, 1H), 8.65-8.60 (m, 2H), 8.34- 8.24 (m, 2H), 7.96-7.90 (m,2H), 7.85-7.68 (m, 4H), 7.56 (t, J = 9.0 Hz, 1H), 7.51-7.44 (m, 2H).DMSO 495.0, 497.0 (M + 1) Method B (NH4HCO3) 95 Method N1 803 ¹H-NMR(400 MHz, DMSO-d₆): δ10.14 (s, 1H), 9.44 (s, 1H), 8.73- 8.63 (m, 1H),8.55 (t, J = 6.5 Hz, 2H), 8.27 (d, J = 4.6 Hz, 1H), 7.96 (d, J = 6.8 Hz,2H), 7.76-7.64 (m, 3H), 7.58-7.52 (m, 2H), 7.31 (t, J = 9.2 Hz, 1H),2.37 (s, 3H). DMSO 459.0, 461.0 (M + 1) Method B (NH4HCO3) 95 Method N1804 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.19 (s, 1H), 9.42 (d, J = 1.5 Hz,1H), 8.74 (d, J = 5.6 Hz, 2H), 8.69- 8.63 (m, 2H), 8.52 (d, J = 8.0 Hz,1H), 8.28 (dd, J = 6.8, 2.6 Hz, 1H), 8.05 (d, J = 7.2 Hz, 1H), 7.96-7.91 (m, 1H), 7.80 (dd, J = 14.6, 6.8 Hz, 3H), 7.59-7.52 (m, 2H). DMSO428.0, 430.0 (M + 1) 214.6 (M/2 + 1) Method A (TFA) 95 Method N1 805¹H-NMR (400 MHz, DMSO-d₆): δ 10.13 (s, 1H), 9.43 (d, J = 1.6 Hz, 1H),8.66 (dd, J = 4.7, 1.6 Hz, 1H), 8.59-8.56 (m, 1H), 8.52 (td, J = 7.9,1.8 Hz, 1H), 8.30 (dd, J = 6.84, 2.60 Hz, 1H), 7.99-7.92 (m, 2H),7.82-7.73 (m, 3H), 7.58- 7.51 (m, 4H), 7.46 (t, J = 7.4 Hz, 1H). DMSO427.1, 429.1 (M + 1) Method A (TFA) 95 Method N1 806 ¹H-NMR (400 MHz,DMSO-d₆): δ 10.13 (s, 1H), 9.45 (s, 1H), 8.67 (dd, J = 4.7, 1.7 Hz, 1H),8.62- 8.49 (m, 2H), 8.29 (dd, J = 6.8, 2.6 Hz, 1H), 8.03-7.88 (m, 2H),7.81- 7.68 (m, 1H), 7.62-7.49 (m, 2H), 7.48-7.30 (m, 3H), 7.04 (dd, J =7.8, 2.1 Hz, 1H), 3.87-3.81 (m, 3H). DMSO 457.1, 459.1 (M + 1) Method A(TFA) 95 Method N1 807 ¹H-NMR (400 MHz, DMSO-d6): δ10.10 (s, 1H), 9.31(d, J = 1.6 Hz, 1H), 8.63 (dd, J = 4.8, 1.7 Hz, 1H), 8.61-8.52 (m, 1H),8.41 (td, J = 8.0, 1.9 Hz, 1H), 8.30 (dd, J = 6.9, 2.6 Hz, 1H),7.97-7.92 (m, 1H), 7.83 (dd, J = 7.2, 1.2 Hz, 1H), 7.73- 7.66 (m, 1H),7.62- 7.40 (m, 3H), 7.36 (dd, J = 7.4, 1.7 Hz, 1H), 7.19 (d, J = 8.1 Hz,1H), 7.10 (t, J = 7.4 Hz, 1H), 3.66 (s, 3H). DMSO 457.1, 459.1 (M + 2)Method B (NH4HCO3) 95 Method N1

Method S:N⁴-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)-N⁶-(3(pyrrolidin-1-yl)propyl)quinazoline-4,6-diamine(xxii-a)

A 2.0 dram reaction vial was charged with6-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine(synthesized as described in Scheme 1 and 4, substituting5-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol, 1.0equiv), 3-(pyrrolidin-1-yl)propan-1-amine (40 mg, 0.345 mmol, 1.5equiv), copper(I) iodide (4.4 mg, 0.023 mmol, 0.1 equiv), L-proline (5.3mg, 0.046 nm tool, 0.2 equiv), and potassium carbonate (96 mg, 0.69mmol, 3.0 equiv) in 1DMF (3 mL). The reaction mixture was heated at 100°C. overnight. After cooling, water was added to the reaction mixture,and the resultant precipitate was collected by filtration. The crudeproduct was purified via prep-TLC (silica, 2000 micron plate, 95%dichloromethane-5% methanol-0.1% NH₄OH) to yield the desired compound asa brown solid (17.2 mg, 15%). LCMS m/z=477.4 (M+1) (Method C) (retentiontime=1.68 min). ¹H NMR (300 MHz, DMSO) δ 9.68 (s, 1H), 9.46 (s, 1H),8.59 (d, J=9.4 Hz, 2H), 8.25 (dd, J=6.8, 2.6 Hz, 1H), 7.93 (dd, J=8.3,3.5 Hz, 1H), 7.69-7.59 (m, 1H), 7.52 (dd, J=11.0, 7.1 Hz, 2H), 7.36-7.19(m, 2H), 6.41 (s, 1H), 3.34 (m, 2H) 2.69 (m, 6H), 2.02-1.82 (m, 2H),1.75 (bs, 4H).

Method T:N-(3-chloro-4-fluorophenyl)-6-(2-morpholinoethoxy)-2-(pyridin-3-yl)quinazolin-4-amine(xxii-b)

A 2.5 dram reaction vial was charged withN-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amine(0.250 g, 0.524 mmol), 2-morpholinoethanol (1 ml, 8.17 mmol) as solvent,copper(I) iodide (0.020 g, 0.105 mmol),racemic-2,2′-diamino-1,1′-binaphthyl (0.030 g, 0.105 mmol), and cesiumcarbonate (0.513 g, 1.573 mmol). The reaction mixture was heated at 110°C. overnight. After cooling, water was added to the reaction mixture,and the resultant precipitate was collected by filtration. The solidresidue was purified via ISCO (silica, 12 g column, 95%dichloromethane-5% methanol-0.1% NH₄OH) to yield the desired compound asa brown solid. The solid was further washed with a mixture of water andsaturated NaHCO₃ solution and dried. The product off the column wasfurther purified by prep TLC (silica gel, 1000 micron, 95%dichloromethane-5% methanol-0.1% NH₄OH) to afford the desired product asa light brown solid (21.2 mg, 8%), LCMS m/z=480.0 (M+1) (Method C)(retention time=2.09 min). ¹H NMR (300 MHz, DMSO) δ 9.81 (s, 1H), 9.47(d, J=1.8 Hz, 1H), 8.66-8.57 (m, 2H), 8.21 (dd, J=6.8, 2.6 Hz, 1H), 7.92(d, J=2.5 Hz, 1H), 7.87 (ddd, J=8.9, 4.3, 2.7 Hz, 1H), 7.81 (d, J=9.1Hz, 1H), 7.57-7.47 (m, 3H), 4.25 (t, J=5.8 Hz, 2H), 3.64-3.55 (m, 4H),2.78 (t, J=5.7 Hz, 2H), 2.55-2.49 (m, 4H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 20 substituting with appropriate amine oralcohol

TABLE 5 Salt Molecular ¹H-NMR Retention LCMS Purity Method for NumberProduct type Mass ¹H-NMR Solvent LCMS Time (min.) Protocol PercentCoupling 808

476.98 1H NMR (300 MHz, DMSO) δ 9.68 (s, 1H), 9.46 (s, 1H), 8.59 (d, J =9.4 Hz, 2H), 8.25 (dd, J = 6.8, 2.6 Hz, 1H), 7.93 (dd, J = 8.3, 3.5 Hz,1H), 7.69-7.59 (m, 1H), 7.52 (dd, J =11.0, 7.1 Hz, 2H), 7.36-7.19 (m,2H), 6.41 (s, 1H), 3.34 (m, 2H), 2.69 (m, DMSO 477.4 (M + 1) 1.68 MethodC 95 Method S 809

492.98 1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 9.46 (s, 1H), 8.60 (td, J= 4.2, 2.4 Hz, 2H), 8.23 (dd, J = 6.8, 2.6 Hz, 1H), 7.90 (ddd, J = 8.9,4.2, 2.6 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.57-7.45 (m, 2H), 7.32 (dd,J = 9.1, 2.2 Hz, 1H), 7.20 (s, 1H), 6.38 (s DMSO 493 (M + 1) 1.97 MethodC 100 Method S 810

423.87 1H NMR (300 MHz, DMSO) δ 9.60 (s, 1H), 9.46 (s, 1H), 8.60 (dd, J= 9.1, 3.1 Hz, 2H), 8.22 (dd, J = 6.9, 25 Hz, 1H), 7.89 (ddd, J = 9.0,4.3, 2.7 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7 58-7.46 (m, 2H), 7.37 (dd,J = 9.1, 2.2 Hz, 1H), 7.25 (s, 1H), 6.40 (t DMSO 423.9 (M + 1) 2.16Method C 100 Method S 811

463.93 1H NMR (300 MHz, DMSO) δ 9.62 (s, 1H), 9.49 (d, J = 1.7 Hz, 1H),8.70- 8.59 (m, 2H), 8.27 (dd, J = 6.9, 2.5 Hz, 1H), 8.19 (dd, J = 9.0,5.0 Hz, 1H), 7.91- 7.82 (m, 1H), 7.57-7.43 (m, 2H), 7.01 (dd, J = 9.0,2.1 Hz, 1H), 6.77 (t, J = 5.3 Hz, 1H), 6.72 DMSO 464.0 (M + 1) 2.19Method C 100 Method S 812

449.91 1H NMR (300 MHz, DMSO) δ 9.65 (s, 1H), 9.49 (d, J = 2.1 Hz, 1H),8.69- 8.59 (m, 2H), 8.27 (dd, J = 6.9, 2.6 Hz, 1H), 8.20 (d, J = 9.0 Hz,1H), 7.87 (ddd, J = 9.0, 4.3, 2.7 Hz, 1H), 7.56- 7.43 (m, 2H), 7.00 (dd,J = 9.1, 2.2 Hz, 1H), 6.79 (d, J = 2.1 Hz, DMSO 449.9 (M + 1) 2.12Method C 100 Method S 813

409.84 1H NMR (300 MHz, DMSO) δ 9.71 (s, 1H), 9.46 (s, 1H), 8.66-8.55(m, 2H), 8.24 (d, J = 4.3 Hz, 1H), 796-7.87 (m, 1H), 7.64 (d, J = 9.1Hz, 1H), 7.58- 7.46 (m, 3H), 7.36 (d, J = 9.0 Hz, 1H), 7.28 (s, 1 H),6.38 (s, 1H), 4.96 (s, 1H), 3.69 (s, 2H), 3.42 DMSO 409.9 (M + 1) 1.86Method C 100 Method S 814

463.93 1H NMR (300 MHz, DMSO) δ 9.59 (s, 1H), 9 45 (d, J = 1.2 Hz, 1H),8.60 (dd, J = 7.4, 5.7 Hz, 2H), 6.23 (dd, J = 6.8, 2.5 Hz, 1H), 7.90(dd, J = 9.0, 2.7 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.57- 7.46 (m, 2H,7.36 (d, J = 9.1 Hz, 1H), 7.19 (s, 1H), 6.38 (s DMSO 464.0 (M + 1) 2.19Method C 95 Method S 815

479.93 1H NMR (300 MHz, DMSO) δ 9.81 (s, 1H), 9.47 (d, J = 1.8 Hz, 1H),8.66- 8.57 (m, 2H), 8.21 (dd, J = 6.8, 2.6 Hz, 1H), 7.92 (d, J = 2.5 Hz,1H), 7.87 (ddd, J = 8.9, 4.3, 2.7 Hz, 1H), 7.81 (d, J = 9.1 Hz, 1H),7.57-7.47 (m, 3H), 4.25 (t, J = 5.8 Hz, 2H), DMSO 480.0 (M + 1) 2.09Method C 91 Method T 816

423.87 1H NMR (300 MHz, DMS0) δ 9.60 (s, 1H), 9.47 (s, 1 H), 8.67-8.55(m, 2H), 8.23 (dd, J = 6.9, 2.5 Hz, 1H), 7.90 (ddd, J = 9.0, 4.3, 2.7Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.58-7.47 (m, 2H), 7.37 (dd, J = 9.1,2.2 Hz, 1H), 7.25 (d, J = 1.3 Hz, 1H), 6.41 (t, J = 5.6 Hz, 1H), 3.63(t, J = 5.7 Hz, 2H), 3.48- 3.35 (m, 5H). DMSO 423.9 (M + 1) Method C 99Method S 817

437.9 1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 9.47 (s, 1H), 8.66-8.55 (m,2H), 8.23 (dd, J = 6.9, 2.5 Hz, 1H), 7.90 (ddd, J = 8.8, 4.3, 2.5 Hz,1H), 7.65 (d, J = 9.0 Hz, 1H), 7.58-7.45 (m, 2H), 7.32 (dd, J = 9.0, 1.8Hz, 1H), 7.21 (s, 1H), 6.34 (t, J = 5.0 Hz, 1H), 3.50 (t, J = 6.1 Hz,2H), 3.31-3.20 (m, 5H), 1.92 (p, J = 6.5 Hz, 2H). DMSO 438.1 (M + 1)Method C 99 Method S 818

449.91 1H NMR (300 MHz, DMSO) δ 9.61 (s, 1H), 9.46 (d, J = 2.1 Hz, 1H),8.65- 8.56 (m, 2H), 8.23 (dd, J = 6.9, 2.6 Hz, 1H), 7.90 (ddd, J = 8.9,4.2, 2.6 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.58- 7.47 (m, 2H), 7.40(dd, J = 8.9, 2.2 Hz, 1H), 7.26 (d, J = 1.7 Hz, 1H), 6.39 (t, J = 5.7Hz, 1H), 4.12 (t, J = 6.2 Hz, 1H), 3.85 (dd, J = 14.2, 7.2 Hz, 1H), 3.70(dd, J = 14.2, 7.7 Hz, 1H), 3.34-3.25 (m, 5H), 2.15-1.99 (m, 1H), 1.97-1.80 (m, 3H), 1.74-158 (m, 2H). DMSO 449.9 (M + 1) Method C 94 Method S819

1H-NMR (300 MHz, DMSO): δ 10.04 (s, 1H), 9.48 (s, 1H), 8.67 (s, 2H),8.43- 8.31 (m, 1H), 8.14-8.01 (m, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.65(s, 1H), 7.54 (dd, J = 9.7 Hz, 2H), 7.35 (d, J = 9.0 Hz, 1H), 6.77 (s,1H), 3.67 (broad doublet, 4H), 3.41 (bs, 2H). 3.08 (d, J = 4.7 Hz, 2H),2.03 (bs, 2H). 1.91 (bs, 2H). DMSO 463.9 (M + 1) Method C 95 Method S

Method U: 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide(xxiii-a)

To a suspension of2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (synthesizedas described in Scheme 1 and 4, substituting 5-methoxy-2-nitrobenzoicacid for 2-nitro-5-propoxy-benzoic acid) (371 mg, 1.0 mmol) in CH₂Cl₂(4.5 mL) was slowly added boron tribromide, 1M solution indichloromethane (4.5 ml, 4.5 mmol) at 0° C. The reaction mixture wasstirred overnight at room temperature after which it was carefullypoured into a vigorously stirring mixture of ice and saturated solutionof aqueous NaHCO₃. The resultant solid was collected by filtration,dried and then stirred in a saturated solution of aqueous NH₄Cl for 1 hafter which the suspension was filtered to give the desired product as ayellowish tan solid (262 mg, 73%). LCMS m/z=357.9 (M+1) (Method C)(retention time=1.68 min), ¹H NMR (300 MHz, DMSO) δ 12.80 (s, 1H), 10.50(s, 1H), 9.57 (s, 1H), 9.15 (d, J=8.5 Hz, 1H), 8.70 (t, J=7.3 Hz, 2H),8.50 (s, 1H), 8.08-7.79 (m, 3H), 7.73 (t, J=7.5 Hz, 1H), 7.57 (dd,J=7.6, 4.8 Hz, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H).

Method V:2-(6-(2-chloroethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide(xxiv-a)

The suspension of2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (50 mg, 0.14mmol), 1-bromo-2-chloroethane (0.015 ml, 0.15 mmol), and potassiumcarbonate (23 mg, 0.17 mmol) in DMF (5 mL) was stirred for 3 days atroom temperature. Water (10 mL) was added to the mixture and extractedwith ethyl acetate (2×10 mL). The combined organic layer was washed withwater (1×20 mL) and brine (1×20 mL) and was dried over MgSO₄. Afterfiltration and evaporation, the crude product was obtained, which waswashed with hexane and dried to give 48 mg of2-(6-(2-chloroethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide aslight brown solid (79%).

Method G4:2-(6-(2-morpholinoethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide(xxv-a)

2-(6-(2-morpholinoethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamidewas prepared from2-(6-(3-chloroethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide andmorpholine in a manner analogous to that described forN-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)propyl)-2-(pyridin-3-yl)quinazolin-4-aminedihydrochloride in Scheme 9 using Method G4 to give 50 mg of2-(6-(2-morpholinoethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamideas light yellow solid. LCMS m/z=485 (M+1) (Method C) (retentiontime=1.71 min). ¹H NMR (300 MHz, DMSO) δ 9.57 (s, 1H), 9.12 (d, J=8.5Hz, 1H), 8.78-8.63 (m, 2H), 8.48 (s, 1H), 8.02-7.93 (m, 2H), 7.88 (d,J=9.0 Hz, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.63-7.49 (m, 3H), 7.20 (t, J=7.6Hz, 1H), 4.29-4.16 (m, 2H), 3.65-3.51 (m, 4H), 3.44-3.21 (m, 2H),2.45-2.31 (m, 4H), 2.06-1.91 (m, 2H).

Method W:2-(6-(2-(2-methylamino)-2-oxoethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide

The suspension of2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (synthesizedas described in Scheme 24) (0.20 g, 0.56 mmol),2-chloro-N-methylacetamide (90 mg, 0.80 mmol), cesium carbonate (0.37 g,112 mmol) and potassium iodide (0.19 g, 1.12 mmol) in DMF (10 mL) wasstirred for 4 days at room temperature. Water (20 mL) was added to themixture. The resultant solid was collected by filtration. The obtainedsolid was washed with CH₂Cl₂-THF (1:1) solution and dried to give 0.11 gof2-(6-(2-(methylamino)-2-oxoethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamideas pale brown solid (46%), LCMS m/z=429 (M+1) (Method C) (retentiontime=1.65 min). ¹H NMR (300 MHz, DMSO) δ 9.58 (s, 1H), 9.12 (d, J=8.4Hz, 1H), 8.82-8.64 (m, 2H), 8.48 (s, 1H), 8.32-8.17 (m, 1H), 8.10-7.87(m, 3H), 7.81-7.49 (m, 4H), 7.21 (t, J=7.5 Hz, 1H), 4.66 (s, 2H), 2.71(d, J=4.5 Hz, 3H).

Method X:2-(6-(2-(dimethylamino)ethoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide

A suspension of2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (synthesizedas described in Scheme 24) (25 mg, 0.07 mmol),2-chloro-N,N-dimethylethylamine hydrochloride (20 mg, 0.14 mmol) andcesium carbonate (68.4 mg, 0.21 mmol) in DMF (1 mL) was stirred at 60°C. overnight. The reaction mixture was cooled to room temperature,diluted with water (5 mL) and extracted with dichloromethane (3×5 mL).The combined organic extracts were dried over Na₂SO₄ and concentrated invacuo. The crude product was purified by prep-TLC (silica, 2000 micronplate, 95% dichloromethane-5% methanol-0.1% NH₄OH) to yield the desiredcompound as a brown solid (12.6 mg, 40%). LCMS m/z=428.9 (M+1) (MethodC) (retention time=1.41 min). ¹H NMR (300 MHz, DMSO) δ 12.99 (s, 1H),9.59 (d, J=1.3 Hz, 1H), 9.12 (d, J=8.4 Hz, 1H), 8.81-8.66 (m, 2H), 8.52(s, 1H), 8.06-7.88 (m, 3H), 7.80-7.53 (m, 4H), 7.22 (t, J=7.6 Hz, 1H),4.46 (s, 2H), 3.35 (s, 2H), 2.69 (s, 6H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 23 substituting with appropriatenucleophile.

TABLE 6 Salt Molecular Number Product type Mass 820

484.550 821

470.523 822

442.470 823

HCl 561.94 824

HCl 598.44 825

469.42 826

483.44 827

HCl 564.91 828

437.85 829

493.92 830

479.93 831

HCl 580.91 832

451.88 833

HCl 566.88 834

366.78 835

428.44 836

484.51 837

442.47 838

357.37 839

2HCl 443.86 840

2HCl 457.89 841

448.48 842

448.48 843

425.48 844

457.89 845

487.91 Starting Starting Salt Number Material R¹ Material R³ ProductType 846

HCl 847

848

849

2HCl 850

2HCl 851

2HCl 852

3HCl 853

3HCl 854

2HCl 855

2HCl 856

2HCl 857

HCl 858

859

HCl 860

2HCl 861

3HCl 862

2HCl 863

2HCl 864

2HCl 865

3HCl 866

4HCl 867

HCl 868

2HCl 869

3HCl 870

2HCl 871

4HCl 872

2HCl 873

3HCl 874

2HCl 875

3HCl 876

CF3COOH 1757

¹H-NMR Retention LCMS Purity Method for Number ¹H-NMR Solvent LCMS Time(min.) Protocol Percent Coupling 820 1H NMR (300 MHz, DMSO) δ DMSO 4851.71 Method C 100 Methods V, 9.57 (s, 1H), 9.12 (d, J = 8.5 Hz, (M + 1)G4 1H), 8.78-8.63 (m, 2H), 8.48 (s, 1H), 8.02-7.93 (m, 2H), 7.88 (d, J =9.0 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.63-7.49 (m, 3H), 7.20 (t, J =7.6 Hz, 1H), 4.29- 4.16 (m, 2H), 3.65-3.51 (m 821 1H NMR (300 MHz, DMSO)δ DMSO 471 1.75 Method C 100 Methods V, 9.58 (s, 1H), 9.24-9.08 (m, 1H),(M + 1) G4 followed 8.82-8.61 (m, 2H), 8.49 (s, 1H), by acylation8.09-7.84 (m, 3H), 7.73 (t, J = with acetyl 7.8 Hz, 1H), 7.67-7.47 (m,3H), chloride/TE 7.19 (t, J = 7.5 Hz, 1H), 4.29- A in DCM 4.09 (m, 2H),3.63-3.42 (m, at rt. 2H), 3.07-2.77 (m, 3H), 2.2 822 1H NMR (300 MHz,DMSO) δ DMSO 443 1.63 Method C 100 Method W 9.58 (s, 1H), 9.16 (d, J =8.4 Hz, (M + 1) 1H), 8.82-8.60 (m, 2H), 8.49 (s, 1H), 8.05-7.80 (m, 3H),7.79- 7.68 (m, 1H), 7.67-7.51 (m, 2H), 7.43 (s, 1H), 7.29-7.12 (m, 1H),5.03 (s, 2H), 3.10 (s, 3H), 2.89 (s, 3H). 823 1H NMR (300 MHz, DMSO) δDMSO 526 2.02 Method C 100 Method W 10.51 (s, 1H), 9.49 (s, 1H), 8.95(M + 1) (d, J = 6.6 Hz, 1H), 8.85 (d, J = 5.0 Hz, 1H), 8.26 (s, 1H),8.10 (s, 1H), 8.03-7.80 (m, 3H), 7.73- 7.51 (m, 2H), 7.19 (d, J = 7.4Hz, 1H), 5.12 (s, 2H), 3.75-3.36 (m, 8H). 824 1H NMR (300 MHz, DMSO) δDMSO 526 2.25 Method C 100 Methods V, 10.98 (s, 1H), 10.59 (s, 1H), 9.50(M + 1) G4 (s, 1H), 8.96 (d, J = 8.1 Hz, 1H), 8.86 (d, J = 5.1 Hz, 1H),8.31 (s, 1H), 8.10 (s, 1H), 8.07-7.93 (m, 2H), 7.92-7.80 (m, 1H), 7.71-7.54 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H), 4.47-4.23 (m, 2 825 1H NMR (300MHz, DMSO) δ DMSO 470 2.04 Method C 100 Method W 9.95 (s, 1H), 9.51 (s,1H), 8.76- (M + 1) 8.56 (m, 2H), 8.26-8.08 (m, 2H), 8.01 (s, 1H),7.95-7.81 (m, 2H), 7.70-7.56 (m, 2H), 7.52 (dd, J = 7.9, 4.9 Hz, 1H),7.17 (d, J = 8.3 Hz, 1H), 4.69 (s, 2H), 2.71 (d, J = 4.5 Hz, 3H). 826 1HNMR (300 MHz, DMSO) δ DMSO 484 1.71 Method D 100 Method W 9.92 (s, 1H),9.51 (s, 1H), 8.74- (M + 1) 8.57 (m, 2H), 8.17 (s, 1H), 8.01 (d, J = 2.5Hz, 1H), 7.96-7.83 (m, 2H), 7.70-7.46 (m, 3H), 7.16 (d, J = 7.0 Hz, 1H),5.03 (s, 2H), 3.06 (s, 3H), 2.88 (s, 3H). 827 1H NMR (300 MHz, DMSO) δDMSO 492 1.81 Method C 100 Methods V, 10.59 (s, 1H), 9.99 (s, 1H), 9.49(M + 1) G4 (s, 1H), 8.97 (d, J = 7.7 Hz, 1H), 8.87 (d, J = 5.3 Hz, 1H),8.33- 8.18 (m, 2H), 8.04-7.83 (m, 3H), 7.68-7.47 (m, 2H), 4.41- 4.27 (m,2H), 3.55-3.43 (m, 2H), 3.34-3.20 (m, 2H), 3.03-2. 828 1H NMR (300 MHz,DMSO) δ DMSO 438 1.65 Method D 100 Method W 9.87 (s, 1H), 9.49 (s, 1H),8.76- (M + 1) 8.53 (m, 2H), 8.32-8.08 (m, 2H), 8.01-7.77 (m, 3H), 7.69-7.43 (m, 3H), 4.67 (s, 2H), 2.71 (d, J = 4.6 Hz, 3H). 829 1H NMR (300MHz, DMSO) δ DMSO 494 1.98 Method C  98 Method W 9.86 (s, 1H), 9.50 (s,1H), 8.76- (M + 1) 8.57 (m, 2H), 8.27 (d, J = 7.0 Hz, 1H), 8.05-7.80 (m,3H), 7.69- 7.45 (m, 3H), 5.04 (s, 2H), 3.78- 3.41 (m, 8H). 830 1H NMR(300 MHz, DMSO) δ DMSO 480 2.20 Method C 100 Method W 9.85 (s, 1H), 9.50(s, 1H), 8.76- (M + 1) 8.53 (m, 2H), 8.26 (dd, J = 6.9, 2.5 Hz, 1H),8.08-7.76 (m, 3H), 7.71-7.41 (m, 3H), 4.98 (s, 2H), 3.52-3.09 (m, 4H),1.37-0.88 (m, 6H). 831 1H NMR (300 MHz, DMSO) δ DMSO 508 2.14 Method C100 Methods V, 10.71 (s, 2H), 9.48 (s, 1H), 9.10- (M + 1) G4 8.95 (m,1H), 8.94-8.79 (m, 1H), 8.36-8.27 (m, 1H), 8.26- 8.16 (m, 1H), 8.07-7.83(m, 3H), 7.68-7.46 (m, 2H), 4.39- 4.18 (m, 2H), 4.05-3.89 (m, 2H), 3.79(t, J = 11.9 Hz, 2H), 3.53- 832 1H NMR (300 MHz, DMSO) δ DMSO 452 1.99Method C 100 Method W 9.85 (s, 1H), 9.50 (s, 1H), 8.71- (M + 1) 8.58 (m,2H), 8.25 (dd, J = 6.8, 2.5 Hz, 1H), 8.01-7.80 (m, 3H), 7.66-7.45 (m,3H), 5.02 (s, 2H), 3.06 (s, 3H), 2.88 (s, 3H). 833 1H NMR (300 MHz,DMSO) δ DMSO 494 2.10 Method C 100 Methods V, 11.18 (s, 1H), 10.93 (s,1H), 9.48 (M + 1) G4 (s, 1H), 9.08 (d, J = 8.4 Hz, 1H), 8.94 (d, J = 5.0Hz, 1H), 8.42 (s, 1H), 8.23 (dd, J = 6.8, 2.5 Hz, 1H), 8.12-7.89 (m,3H), 7.63 (d, J = 9.1 Hz, 1H), 7.54 (t, J = 9.1 Hz, 1H), 4.45-4.26 (m,834 1H NMR (300 MHz, DMSO) δ DMSO 367 1.69 Method D 100 Method U9.98-9.59 (m, 1H), 9.53-9.41 (M + 1) (m, 1H), 8.71-8.48 (m, 2H), 8.31(dd, J = 6.9, 2.5 Hz, 1H), 8.01-7.85 (m, 1H), 7.83-7.66 (m, 2H),7.59-7.35 (m, 3H). 835 1H NMR (300 MHz, DMSO) δ DMSO 429 1.65 Method C100 Method W 9.58 (s, 1H), 9.12 (d, J = 8.4 Hz, (M + 1) 1H), 8.82-8.64(m, 2H), 8.48 (s, 1H), 8.32-8.17 (m, 1H), 8.10- 7.87 (m, 3H), 7.81-7.49(m, 4H), 7.21 (1, J = 7.5 Hz, 1H), 4.66 (s, 2H), 2.71 (d, J = 4.5 Hz,3H). 836 1H NMR (300 MHz, DMSO) δ DMSO 485 1.72 Method C  91 Method W9.58 (s, 1H), 9.13 (d, J = 8.3 Hz, (M + 1) 1H), 8.78-8.64 (m, 2H), 8.50(s, 1H), 8.02-7.80 (m, 3H), 7.73 (t, J = 7.9 Hz, 1H), 7.68-7.53 (m, 2H),7.49 (s, 1H), 7.20 (t, J = 7.5 Hz, 1H), 5.07 (s, 2H), 3.79-3.40 (m, 8H).837 1H NMR (300 MHz, DMSO) δ DMSO 443 1 .69 Method C 100 Method W 9.59(s, 1H), 9.12 (d, J = 8.4 Hz, (M + 1) 1H), 8.78-8.63 (m, 1H), 8.49 (s,1H), 8.29 (s, 1H), 8.11-7.88 (m, 2H), 7.79-7.47 (m, 4H), 7.26- 7.14 (m,1H), 4.58 (s, 2H), 3.27- 3.08 (m, 2H), 1.18-0.93 (m, 3H). 838 1H NMR(300 MHz, DMSO) δ DMSO 357.9 1.68 Method C 100 Method U 12.80 (s, 1H),10.50 (s, 1H), 9.57 (M + 1) (s, 1H), 9.15 (d, J = 8.5 Hz, 1H), 8.70 (t,J = 7.3 Hz, 2H), 8.50 (s, 1H), 8.08-7.79 (m, 3H), 7.73 (t, J = 7.5 Hz,1H), 7.57 (dd, J = 7.6, 4.8 Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.19 (t,J = 7.6 Hz, 1H). 839 1H NMR (300 MHz, DMSO) δ DMSO 443.9 1.87 Method C100 Method U 10.57 (s, 1H), 9.49 (s, 1H), 8.97 (M + 1) (d, J = 8.2 Hz,1H), 8.89 (s, 1H), 8.81 (s, 1H), 8.16 (ddd, J = 12.2, 10.9, 5.2 Hz, 3H),8.05 (d, J = 2.3 Hz, 1H), 8.00-7.86 (m, 3H), 7.55 (1, J = 9.1 Hz, 1H),6.55 (d, J = 9.5 Hz, 1H). 840 1H NMR (300 MHz, DMSO) δ DMSO 458.0 2.12Method D 100 Method U 10.27 (s, 1H), 9.47 (s, 1H), 9.09 (M + 1) (d, J =8.1 Hz, 1H), 8.91 (d, J = 4.4 Hz, 1H), 8.56 (s, 1H), 8.18- 8.08 (m, 2H),8.01 (d, J = 6.3 Hz, 3H), 7.96-7.89 (m, 1H), 7.49 (t, J = 9.1 Hz, 1H),6.52 (d, J = 9.6 Hz, 1H), 2.71 (s, 3H). 841 1H NMR (300 MHz, DMSO) δDMSO 449.2 1.93 Method C  96 Method X 13.08 (s, 1H), 9.59 (s, 1H), 9.16(M + 1) (d, J = 8.4 Hz, 1H), 8.88-8.44 (m, 5H), 8.12-7.85 (m, 4H), 7.73(q, J = 8.7 Hz, 3H), 7.58 (dd, J = 7.9, 4.8 Hz, 1H), 7.49 (dd, J = 7.8,4.8 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 5.36 (s, 2H). 842 1H NMR (300MHz, DMSO) δ DMSO 449.1 1.89 Method C 100 Method X 13.00 (s, 1H), 9.57(s, 1H), 9.12 (M + 1) (d, J = 8.4 Hz, 1H), 8.76-8.60 (m, 4H), 8.50 (s,1H), 8.03-7.89 (m, 3H), 7.68 (dd, J = 15.6, 5.2 Hz, 3H), 7.57 (t, J =4.6 Hz, 3H), 7.19 (t, J = 7.6 Hz, 1H), 5.37 (s, 2H). 843 1H NMR (300MHz, DMSO) δ DMSO 426.2 2.46 Method C 100 Method X 12.95 (s, 1H), 9.56(s, 1H), 9.10 (M + 1) (d, J = 8.4 Hz, 1H), 8.75-8.64 (m, 2H), 8.46 (s,1H), 7.98-7.91 (m, 2H), 7.85 (dd, J = 9.0, 0.8 Hz, 1H), 7.71 (t, J = 7.9Hz, 1H), 7.61-7.48 (m, 3H), 7.18 (t, J = 7.6 Hz, 1H), 4.12 (d, J = 6.6Hz, 2H), 2.84 (dd, J = 14.3, 7.4 Hz, 1H), 2.18-2.05 (m, 2H), 1.97- 1.84(m, 5H). 844 1H-NMR (400 MHz, DMSO-d6): DMSO 458.1, 460.1 Method A  95Method X δ 9.95 (s, 1H), 9.54 (d, J = 1.6 (M + 1) Hz, 1H), 8.82 (d, J =1.7 Hz, 1H), 229.6, 230.3 8.78-8.59 (m, 3H), 8.29 (dd, J = (M/2 + 1)6.8, 2.6 Hz, 1H), 8.16 (d, J = 2.5 Hz, 1H), 8.06-7.86 (m, 3H), 7.69 (dd,J = 9.1, 2.5 Hz, 1H), 7.64-7.47 (m, 3H), 5.37 (s, 2H). 845 1H-NMR (400MHz, DMSO-d6): DMSO 488.1, 490.1 Method A  95 Method X δ 9.74 (s, 1H),9.34 (s, 1H), 8.57- (M + 1) 8.41 (m, 2H), 8.22 (d, J = 2.2 244.6, 245.4Hz, 1H), 8.10 (dd, J = 6.8, 2.6 (M/2 + 1) Hz, 1H), 7.95 (d, J = 2.5 Hz,1H), 7.80-7.63 (m, 3H), 7.53-7.30 (m, 3H), 6.82-6.68 (m, 1H), 5.07 (s,2H), 3.71 (s, 3H). ¹H NMR Purity Method Number ¹H NMR Solvent percent ofCoupling 846 1H NMR (400 MHz, DMSO) δ 9.31 (d, J = 1.7 Hz, DMSO >98Method X 1H), 8.83-8.76 (m, 1H), 8.76-8.67 (m, 1H), using K₂CO₃ 8.07 (d,J = 9.2 Hz, 1H), 7.86 (dd, J = 6.3, 2.8 Hz instead of 1H), 7.83-7.73 (m,2H), 7.70 (d, J = 2.8 Hz, 1H), Cs₂CO₃ 7.68-7.61 (m, 1H), 7.60-7.52 (m,1H), 5.12 (s, 2H), 3.05 (s, 3H), 2.88 (s, 3H). 847 1H NMR (400 MHz,DMSO) δ 9.28 (dd, J = 2.2, 0.8 DMSO >98 Method X Hz, 1H), 8.65 (dd, J =4.8, 1.7 Hz, 1H), 8.50- using K₂CO₃ 8.44 (m, 1H), 8.04 (d, J = 9.2 Hz,1H), 7.92 (d, J = instead of 2.7 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.75(dd, J = Cs₂CO₃ 9.2, 2.9 Hz, 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.56 (dd, J= 8.8, 2.7 Hz, 1H), 7.52 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 5.10 (s, 2H),3.05 (s, 3H), 2.88 (s, 3H). 848 ¹H NMR (400 MHz, CDCl₃) δ 9.45 (dd, J =2,1, 0.8 CDCl3 >98 Method X Hz, 1H), 8.61 (dd, J = 4.8, 1.7 Hz, 1H),8.59- using K₂CO₃ 8.53 (m, 1H), 8.01 (dd, J = 8.7, 0.8 1H), 7.72-instead of 7.62 (m, 2H), 7.56-7.47 (m, 2H), 7.39-7.29 Cs₂CO₃ (m, 4H),4.90 (s, 2H), 3.15 (s, 3H), 3.04 (s, 3H). 849 1H NMR (300 MHz, DMSO) δ13.01-11.72 (m, DMSO >98 W 1H), 9.70 (s, 1H), 9.40-9.30 (m, 1H), 8.99(d, J = 4.5 Hz, 1H), 8.23 (d, J = 2.6 Hz, 1H), 8.12 (dd, J = 8.1, 5.5Hz, 1H), 8.06-7.98 (m, 2H), 7.92 (d, J = 9.1 Hz, 1H), 7.84 (d, J = 4.9Hz, 1H), 7.63 (dd, J = 9.1, 2.6 Hz, 1H), 7.56-7.49 (m, 2H), 5.05 (s,3H), 3.11 (s, 3H), 2.92 (s, 3H). 850 1H NMR (300 MHz, DMSO) δ 9.74 (d, J= 1.8 Hz, DMSO >98 W 1H), 9.47-9.36 (m, 1H), 9.01 (dd, J = 5.5, 1.2 Hz,1H), 8.28 (d, J = 2.6 Hz, 1H), 8.16 (dd, J = 8.2, 5.5 Hz, 1H), 8.06-7.93(m, 3H), 7.81 (s, 1H), 7.66 (dd, J = 9.1, 2.6 Hz, 1H), 7.54-7.44 (m,2H), 7.42-7.33 (m, 1H), 5.07 (s, 2H), 3.11 (s, 3H), 2.91 (s, 3H). 851 1HNMR (300 MHz, DMSO) δ 12.67 (s, 1H), 9.31- DMSO >98 W 9.25 (m, 1H), 8.73(dd, J = 4.8, 1.6 Hz, 1H), 8.52- 8.42 (m, 1H), 7.74 (d, J = 3.9 Hz, 1H),7.66 (d, J = 2.9 Hz, 1H), 7.61-7.47 (m, 4H), 7.45-7.31 (m, 3H), 5.27 (s,2H), 3.30 (s, 3H). 852 1H NMR (300 MHz, DMSO) δ 9.56 (d, J = 1.8 Hz,DMSO >98 W 1H), 9.25 (d, J = 8.2 Hz, 1H), 9.08-8.98 (m, 1H), 8.81 (d, J= 4.5 Hz, 1H), 8.31 (td, J = 7.8, 1.6 Hz, 1H), 8.20-8.08 (m, 1H), 7.95(d, J = 7.9 Hz, 1H), 7.88-7.63 (m, 4H), 7.47 (d, J = 2.1 Hz, 1H), 7.30(dd, J = 8.6, 2.2 Hz, 1H), 5.60 (s, 2H), 4.63 (t, J = 7.8 Hz, 2H), 3.25(t, J = 7.7 Hz, 2H). 853 1H NMR (300 MHz, DMSO) δ 9.56 (d, J = 1.8 Hz,DMSO >98 W 1H), 9.22 (d, J = 8.3 Hz, 1H), 9.00 (dd, J = 5.5, 1.3 Hz,1H), 8.80 (d, J = 4.4 Hz, 1H), 8.29 (td, J = 7.8, 1.6 Hz, 1H), 8.21-8.05(m, 2H), 8.00-7.66 (m, 5H), 7.29 (dd, J = 8.4, 2.6 Hz, 1H), 7.12 (td, J= 9.0, 2.8 Hz, 1H), 5.59 (s, 2H), 4.66 (t, J = 7.8 Hz, 2H), 3.25 (t, J =7.6 Hz, 2H). 854 1H NMR (300 MHz, DMSO) δ 9.55 (d, J = 1.8 Hz, DMSO >98W 1H), 9.30-9.18 (m, 1H), 9.00 (dd, J = 5.5, 1.3 Hz, 1H), 8.18-3.02 (m,2H), 7.87 (dd, J = 8.8, 4.8 Hz, 1H), 7.71 (dd, J = 9.2, 2.7 Hz, 1H),7.49 (d, J = 2.7 Hz, 1H), 7.29 (dd, J = 8.4, 2.6 Hz, 1H), 7.13 (td, J =9.1, 2.8 Hz, 1H), 5.05 (s, 2H), 4.63 (d, J = 7.7 Hz, 2H), 3.25 (t, J =7.5 Hz, 2H), 3.02 (s, 3H), 2.86 (s, 3H). 855 1H NMR (300 MHz, DMSO) δ9.55 (d, J = 1.7 Hz, DMSO >98 W 1H), 9.15 (d, J = 8.2 Hz, 1H), 8.99-8.90(m, 1H), 8.10-7.98 (m, 2H), 7.77 (dd, J = 8.9, 4.7 Hz, 1H), 7.67 (dd, J= 9.1, 2.7 Hz, 1H), 7.51 (d, J = 2.6 Hz, 1H), 7.28 (dd, J = 8.4, 2.7 Hz,1H), 7.12 (dd, J = 10.3, 7.7 Hz, 1H), 4.70 (t, J = 7.8 Hz, 2H),4.23-4.14 (m, 2H), 3.26 (t, J = 7.9 Hz, 2H), 1.41 (t, J = 6.9 Hz, 3H).856 1H NMR (300 MHz, DMSO) δ 9.54 (d, J = 1.7 Hz, DMSO >98 W 1H), 9.19(d, J = 8.1 Hz, 1H), 8.98 (d, J = 4.3 Hz, 1H), 8.15-8.02 (m, 2H),7.90-7.72 (m, 2H), 7.60 (d, J = 2.6 Hz, 1H), 7.53-7.41 (m, 1H), 7.40-7.05 (m, SH), 5.34 (s, 2H), 4.59 (t, J = 7.8 Hz, 2H), 3.22 (t, J = 7.5Hz, 2H). 857 ¹H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 9.49 DMSO >98Method W (d, J = 1.8 Hz, 1H), 9.11 (d, J = 8.0 Hz, 1H), 8.95 (dd, J =5.4, 1.3 Hz, 1H), 8.26 (dd, J = 24.6, 3.5 Hz, 2H), 8.12-7.95 (m, 3H),7.71 (dt, J = 9.1, 4.5 Hz, 2H), 7.56 (dd, J = 19.7, 9.1 Hz, 1H), 4.75(s, 2H), 2.72 (d, J = 5.0 Hz, 3H). 858 ¹H NMR (400 MHz, DMSO) δ 9.77 (brs, J = 81.7 DMSO >98 Method W Hz, 1H), 9.50 (d, J = 1.5 Hz, 1H),8.71-8.57 (m, 2H), 8.22-8.07 (m, 1H), 7.97 (t, J = 5.1 Hz, 1H), 7.87 (d,J = 9.1 Hz, 1H), 7.81-7.39 (m, 4H), 5.01 (s, 2H), 3.07 (s, 3H), 2.90 (s,3H). 859 ¹H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 9.50 DMSO >98 Method W(d, J = 1.7 Hz, 1H), 9.01 (d, J = 3.1 Hz, 1H), 8.90 (dd, J = 5.3, 1,5Hz, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.20-8.09 (m, 1H), 7.95 (dd, J = 8.5,4.7 Hz, 2H), 7.83-7.74 (m, 1H), 7.67 (dd, J = 9.1, 2.6 Hz, 1H), 7.55(dd, J = 19.7, 9.1 Hz, 1H), 5.15 (s, 2H), 4.29-3.00 (m, 8H). 860 ¹H NMR(400 MHz, DMSO) δ 10.39 (s, 1H), 9.51 DMSO >98 Method W (d, J = 1.6 Hz,1H), 8,81 (dd, J = 19.3, 6.0 Hz, 2H), 8.29 (s, 1H), 8.16 (dd, J = 10.6,7.5 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.77 (s, 2H), 7.69-7.51 (m, 2H),4.67 (s, 2H), 3.99 (s, 2H), 3.81 (br s, 4H), 3.70 (br s, 4H). 861 ¹H NMR(400 MHz, DMSO) δ 10.82 (s, 1H), 9.50 DMSO >98 Method W (d, J = 1.3 Hz,1H), 9.02 (d, J = 8.0 Hz, 1H), 8.90 (d, J = 4.4 Hz, 1H), 8.46 (s, 1H),8.21-8.10 (m, 1H), 8.03-7.90 (m, 2H), 7.84 (d, J = 8.7 Hz, 1H), 7.68(dd, J = 9.1, 2.3 Hz, 1H), 7.55 (dd, J = 19.6, 9.3 Hz, 1H), 4,67 (s,2H), 3,23-3.05 (m, 6H), 2.10-1.78 (m, 4H). 862 ¹H NMR (400 MHz, DMSO) δ10.77 (s, 1H), 9.49 DMSO >98 Method W (d, J = 1.6 Hz, 1H), 9.12 (d, J =8.1 Hz, 1H), 8.99- 8.91 (m, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.12- 7.99(m, 3H), 7.78-7.71 (m, 1H), 7.66-7.54 (m, 2H), 4.02 (d, J = 6.5 Hz, 2H),2.24-2.00 (m, 1H), 1.07 (d, J = 6.7 Hz, 6H). 863 ¹H NMR (400 MHz, CDCl₃)δ 10.71 (s, 1H), 9.80 (s, DMSO >98 Method W 1H), 9.40 (d, J = 8.2 Hz,1H), 3.95 (d, J = 5.2 Hz, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.24 (d, J =9.2 Hz, 1H), 8.08 (dd, J = 8.0, 5.6 Hz, 1H), 7.86-7.76 (m, 1H), 7.69 (d,J = 8.7 Hz, 1H), 7.56 (d, J = 8.8, 2.2 Hz, 1H), 7.31 (s, 1H), 5.08 (s,2H), 3.69 (t, J = 6.8 Hz, 2H), 3.55 (t, J = 6.9 Hz, 2H), 2.13-2.01 (m,2H), 1.98-1.35 (m, 2H). 864 1H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 9.50DMSO >98 Method W (d, J = 1.9 Hz, 1H), 9.12 (d, J = 8.2 Hz, 1H), 8.96(dd, J = 5.5, 1.4 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 8.20 (d, J = 8.0Hz, 1H), 8.15-7.97 (m, 3H), 7.75 (ddd, J = 11.9, 7.4, 3.3 Hz, 2H), 7.56(dt, J = 10.6, 9.1 Hz, 1H), 4.74 (s, 2H), 4.07-3.93 (m, 1H), 1.13 (d, J= 6.6 Hz, 6H).. 865 ¹H NMR (400 MHz, DMSO) δ 10.8 (s, 1H), 9.51 DMSO >98Method W (d, J = 1.8 Hz, 1H), 9.15 (d, J = 8.2 Hz, 1H), 8.97 (dd, J =5.4, 1.3 Hz, 1H), 8.82-8.74 (m, 1H), 8.55 (d, J = 2.6 Hz, 1H), 8.23-8.19(m, 1H), 8.16- 8.01 (m, 3H), 7.94 (d, J = 7.9 Hz, 1H), 7.85- 7.75 (m,2H), 7.70 (dd, J = 7.0, 5.8 Hz, 1H), 7.61- 7.49 (m, 1H), 5,63 (s, 2H).866 ¹H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 9.50 DMSO >98 Method W (d, J= 1.8 Hz, 1H), 9.11 (d, J = 8.1 Hz, 1H), 8.95 (d, J = 5.4 Hz, 1H), 8.76(d, J = 5.0 Hz, 1H), 8.42 (s, 1H), 8.18 (t, J = 7.8 Hz, 1H), 8.08-7.96(m, 4H), 7.89 (d, J = 7.8 Hz, 1H), 7.80 (dd, J = 9.1, 2.6 Hz, 1H), 7.64(t, J = 8.2 Hz, 2H), 7.24 (d, J = 8.3 Hz, 1H), 5.57 (s, 2H). 867 1H NMR(300 MHz, DMSO) d 9.58 (s, 1H), 9.05 (d, DMSO  94 Method X J = 8.2 Hz,1H), 8.98 (d, J = 8.1 Hz, 1H), 8.88 (d, (K2CO3, DMF- J = 5.1 Hz, 1H),8.47 (s, 1H), 8.05-7.85 (m, 4H), THF (1:1), rt) 7.71 (m, 1H), 7.61 (d, J= 8.1 Hz, 2H), 7.24 (dd, J = 7.6 Hz, 1H). 868 1H NMR (300 MHz, DMSO) δ13.07 (s, 1H), 9.59 DMSO  99 Method X (d, J = 1.4 Hz, 1H), 9.13 (d, J =8.1 Hz, 1H), 8.97 (d, J = 7.8 Hz, 1H), 8.92 (d, J = 4.1 Hz, 1H), 8.49(s, 1H), 8.08-7.92 (m, 4H), 7.80-7.64 (m, 3H), 7.26 (td, J = 7.8, 1.1Hz, 1H), 7.14 (d, J = 1.5 Hz, 1H), 7.09 (dd, J = 7.9, 1.6 Hz, 1H), 6.95(d, J = 7.9 Hz, 1H), 6.03 (s, 2H), 5.19 (s, 2H). 869 ¹H-NMR (400 MHz,DMSO-d₆): δ 9.67 (s, 1H), 9.40 DMSO  98 Method X (d, J = 7.6 Hz, 1H),9.01 (d, J = 8.4 Hz, 2H), 8.93 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 7.6 Hz,1H), 8.22 (t, J = 7.2 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.97- 7.92 (m,2H), 7.79-7.71 (m, 3H), 7.33 (t, J = 8.0 Hz, 1H), 5.54 (s, 2H). 870¹H-NMR (400 MHz, CD3OD): δ 9.62 (d, J = 6.9 Hz, MeOD  95 Method W 1H),9.40 (d, J = 8.2 Hz, 1H), 8.99 (d, J = 5.3 Hz, 1H), 8.82 (t, J = 8.2 Hz,1H), 8.22 (dd, J = 8.1, 5.7 Hz, 1H), 8.02-7.88 (m, 2H), 7.76-7.60 (m,3H), 7.31 (t, J = 7.6 Hz, 1H), 4.81 (q, J = 8.1 Hz, 2H). 871 ¹H-NMR (400MHz, DMSO-d₆): δ 12.96 (s, 1H), DMSO-d₆  95 Method X 9.59 (s, 1H), 9.24(d, J = 8.1 Hz, 1H), 9.00 (s, 1H), 8.80 (d, J = 5.7 Hz, 2H), 8.50 (s,1H), 8.22 (t, J = 7.2 Hz, 1H), 8.09 (d, J = 9.2 Hz, 2H), 7.99- 7.79 (m,5H), 7.74-7.54 (m, 6H), 7.30 (t, J = 7.5 Hz, 1H), 5.55 (s, 2H). 872¹H-NMR (400 MHz, DMSO-d₆): δ 12.82 (s, 1H), DMSO  95 Method X 9.58 (s,1H), 9.13 (d, J = 6.9 Hz, 1H), 8.93 (s, 1H), 8.82 (d, J = 8.0 Hz, 1H),8.43 (s, 1H), 8.04- 7.88 (m, 4H), 7.74-7.69 (m, 3H), 7.28 (t, J = 7.6Hz, 1H), 7.01-6.91 (m, 2H), 6.87-6.85 (m, 2H), 4.74-4.70 (m, 1H),4.55-4.53 (m, 1H), 4.50- 4.47 (m, 1H), 4.29-4.24 (m, 1H). 873 ¹H-NMR(400 MHz, DMSO-d₆): δ 13.07 (s, 1H), DMSO  95 Method X 9.61 (s, 1H),9.05-9.00 (m, 2H), 8.88 (d, J = 4 Hz, 1H), 8.51 (s, 1H), 8.25 (s, 1H),8.11-8.08 (m, 2H), 7.99-7.97 (m, 3H), 7.91-7.88 (m, 2H), 7.76-7.72 (m,2H), 7.47 (dd, J = 2.0, 8.8 Hz, 1H), 7.27 (t, J = 8.8 Hz, 1H), 5.61 (s,2H). 874 ¹H-NMR (400 MHz, DMSO-d₆): δ 12.89 (s, 1H), DMSO  95 Method X10.72 (s, 1H), 9.83 (s, 1H), 9.38 (d, J = 8.2 Hz, 1H), 9.22 (d, J = 5.6Hz, 1H), 9.03 (d, J = 8.3 Hz, 1H), 8.51 (s, 1H), 8.37-8.27 (m, 1H),8.02-7.86 (m, 3H), 7.71 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H),7.51 (s, 1H), 7.25 (t, J = 7.5 Hz, 1H), 4.71 (d, J = 7.3 Hz, 2H), 1.56(s, 1H), 0.81-0.64 (m, 4H). 875 ¹H-NMR (400 MHz, DMSO-d₆): δ 12.88 (s,1H), DMSO  95 Method X 9.57 (s, 1H), 9.24 (d, J = 8.1 Hz, 1H), 9.01 (d,J = 5.3 Hz, 1H), 8.73 (d, J = 8.2 Hz, 1H), 8.49 (s, 1H), 8.37 (t, J =7.8 Hz, 1H), 8.10 (dd, J = 11.3, 7.0 Hz, 2H), 7.97 (d, J = 7.8 Hz, 2H),7.86 (s, 2H), 7.80 (d, J = 7.1 Hz, 2H), 7.71 (t, J = 7.8 Hz, 1H), 7.30(t, J = 7.5 Hz, 1H), 5.65 (s, 2H); 2.78 (s, 3H). 876 ¹H-NMR (400 MHz,DMSO-d₆): δ 12.93 (s, 1H), DMSO  95 Method W 10.74 (s, 1H), 9.75 (s,1H), 9.40 (s, 1H), 9.05 (d, J = 8.0 Hz, 2H), 8.99 (d, J = 6.0 Hz, 1H),7.99 (s, 1H), 7.98-7.96 (m, 1H), 7.89-7.86 (m, 2H), 7.72-7.51 (m, 2H),7.24 (t, J = 6.0 Hz, 1H), 5.84 (s, 2H), 3.60-3.56 (m, 2H), 3.43-3.39 (m,2H), 2.06-2.01 (m, 2H), 1.99-1.84 (m, 2H). 1757  ¹H NMR (400 MHz, DMSO)δ 9.32-9.27 (m, 1H), DMSO >98 Method W 8.66 (dd, J = 4.8, 1.7 Hz, 1H),8.64-8.60 (m, using K₂CO₃ 1H), 8.50-8.43 (m, 1H), 8.10-8.03 (m, 1H),instead of 7.93-7.80 (m, 4H), 7.68-7.60 (m, 2H), 7.59- Cs₂CO₃ 7.49 (m,2H), 7.39 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 5.43 (s, 2H).

Method Y: 2-Amino-N-cyclohexyl-benzamide (ii-b)

To a dry reaction vial was added cyclohexylamine (40 uμmol, 1.0 eq) andPS-carbodiimide resin (72 μmol, 1.8 eq). The solution of 2-amino-benzoicacid (44 μmol, 1.1 eq), diisopropyl ethyl amine (10 μLl) and HOBt (44μmol, 1.1 eq) in THF (500 μL) was added to the above vial. The reactionmixture was heated at 40° C. for 6 h on a shaker. The resin was removedby filtration and washed with 10% MeOH/CH₂Cl₂. The solvent was removedin vacuo and the residue was applied to solid phase extraction cartridge(basic silica, 200 mg) and eluted with 50% EtOAc/CH₂Cl₂. After removalof the solvents, the crude 2-amino-N-cyclohexyl-benzamide was obtainedand used for the following reaction.

Method Z:N-Cyclohexyl-2-(6-methoxy-2-pyridin-3-yl-quinazolin-4-ylamino)-benzamide(xiv-f)

To the crude amide was added the solution of4-chloro-6-methoxy-2-pyridin-3-yl-quinazoline (20 μmol) in 2-propanol(200 μL). The mixture was refluxed for 8 h. After evaporation, theresidue was dissolved in 5% TFA/MeOH-DMF (1:1) and purified by PREP-HPLCCondition D. The target fraction was lyophilized to afford the titledcompound whose structure was finally confirmed by LCMS using LCMS MethodE.

The compounds in the following table were prepared in a manner analogousto that described in Scheme 27, replacing cyclohexylamine with theappropriate amine.

TABLE 7 Exact LCMS Method of Number Product Mass (M + 1) Coupling 877

489 490 Methods Y, Z 878

453 454 Methods Y, Z 879

495 496 Methods Y, Z 880

495 496 Methods Y, Z 881

491 492 Methods Y, Z 882

491 492 Methods Y, Z 883

493 494 Methods Y, Z 884

467 468 Methods Y, Z 885

441 442 Methods Y, Z 886

529 530 Methods Y, Z 887

543 544 Methods Y, Z 888

543 544 Methods Y, Z 889

543 544 Methods Y, Z 890

487 488 Methods Y, Z 891

493 494 Methods Y, Z 892

467 468 Methods Y, Z 893

441 442 Methods Y, Z 894

529 530 Methods Y, Z 895

543 544 Methods Y, Z 896

543 544 Methods Y, Z 897

543 544 Methods Y, Z 898

487 488 Methods Y, Z 899

467 468 Methods Y, Z 900

501 502 Methods Y, Z 901

465 466 Methods Y, Z 902

435 436 Methods Y, Z 903

519 520 Methods Y, Z 904

487 488 Methods Y, Z 905

487 488 Methods Y, Z 906

467 468 Methods Y, Z 907

501 502 Methods Y, Z 908

465 466 Methods Y, Z 909

435 436 Methods Y, Z 910

519 520 Methods Y, Z

Method Z: Synthesis ofN-(4-chlorophenyl)-6-methoxy-2-(pyridin-3-yl)quinazolin-4-amine (vi-k)

To 4-chloroaniline (24 μmol) was added the solution of4-chloro-6-methoxy-2-pyridin-3-yl-quinazoline (20 mmol) in 2-propanol(200 μL). The mixture was refluxed for 8 h. After evaporation, theresidue was dissolved in 5% TFA/MeOH-DMF (1:1) and purified by PREP-HPLCCondition D. The target fraction was lyophilized to afford the titledcompound as the TFA salt whose structure was finally confirmed by LCMSusing LCMS Method E.

The compounds in the following table were prepared in a manner analogousto that described in Scheme 29, replacing 4-chloroaniline with theappropriate aniline.

TABLE 8 Exact LCMS Method of Number Product Mass (M + 1) Coupling 911

362 363 Method Z 912

358 359 Method Z 913

396 397 Method Z 914

392 393 Method Z 915

388 389 Method Z 916

372 373 Method Z 917

388 389 Method Z 918

342 343 Method Z 919

353 354 Method Z 920

416 417 Method Z 921

396 397 Method Z 922

396 397 Method Z 923

356 357 Method Z 924

364 365 Method Z 925

372 373 Method Z 926

392 393 Method Z 927

376 377 Method Z 928

426 427 Method Z 929

407 408 Method Z 930

430 431 Method Z 931

440 441 Method Z 932

392 393 Method Z 933

380 381 Method Z 934

380 381 Method Z 935

380 381 Method Z 936

434 435 Method Z 937

421 422 Method Z 938

378 379 Method Z 939

376 377 Method Z 940

387 388 Method Z 941

414 415 Method Z 942

392 393 Method Z 943

380 381 Method Z 944

390 391 Method Z 945

428 429 Method Z 946

428 429 Method Z 947

391 392 Method Z 948

356 357 Method Z 949

377 378 Method Z 950

392 393 Method Z 951

368 369 Method Z 952

397 398 Method Z 953

441 442 Method Z 954

379 380 Method Z 955

401 402 Method Z 956

383 384 Method Z 957

382 383 Method Z 958

379 380 Method Z 959

393 394 Method Z 960

411 412 Method Z 961

379 380 Method Z 962

370 371 Method Z 963

385 386 Method Z 964

427 428 Method Z 965

395 396 Method Z 966

379 380 Method Z 967

402 403 Method Z 968

384 385 Method Z

Method Z: Synthesis of6-chloro-N-(4-chlorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (vi-c)

To 4-chloroaniline (24 μmol) was added the solution of4,6-dichloro-2-(pyridin-3-yl)quinazoline (20 μmol) in 2-propanol (200μL). The mixture was refluxed for 8 h. After evaporation, the residuewas dissolved in 5% TFA/MeOH-DMF (1:1) and purified by PREP-HPLCCondition D. The target fraction was lyophilized to afford the titledcompound as the TFA salt whose structure was finally confirmed by LCMSusing LCMS Method E.

The compounds in the following table were prepared in a manner analogousto that described in Scheme 31, replacing 4-chloroaniline with theappropriate aniline,

TABLE 9 Exact LCMS Method of Number Product Mass (M + 1) Coupling 969

366 367 Method Z 970

362 363 Method Z 971

366 367 Method Z 972

346 347 Method Z 973

392 393 Method Z 974

392 393 Method Z 975

419 420 Method Z 976

392 393 Method Z 977

346 347 Method Z 978

350 351 Method Z 979

350 351 Method Z 980

350 351 Method Z 981

376 377 Method Z 982

420 421 Method Z 983

360 361 Method Z 984

360 361 Method Z 985

360 361 Method Z 986

360 361 Method Z 987

368 369 Method Z 988

368 369 Method Z 989

380 381 Method Z 990

376 377 Method Z 991

396 397 Method Z 992

380 381 Method Z 993

430 431 Method Z 994

392 393 Method Z 995

396 397 Method Z 996

380 381 Method Z 997

382 383 Method Z 998

384 385 Method Z 999

465 466 Method Z 1000

357 358 Method Z 1001

396 397 Method Z 1002

425 426 Method Z 1003

380 381 Method Z 1004

434 435 Method Z 1005

396 397 Method Z 1006

384 385 Method Z 1007

446 447 Method Z 1008

415 416 Method Z 1009

381 382 Method Z 1010

381 382 Method Z 1011

396 397 Method Z

N-(3-Carbamoylthiophen-2-yl)nicotinamide (iii-b)

To a solution of 2-aminothiophene-3-carboxamide (800 mg, 5.63 mmol, 1.0eq.) in THF (15 mL) and Et₃N (626 mg, 6.19 mmol, 1.1 eq.) was addednicotinoyl chloride (795 mg, 5.63 mmol, 1.0 eq.) in anhydrous THF (15mL) dropwise. The resulted mixture was stirred at room temperatureovernight. After the reaction was completed, the volatiles wereevaporated. The residue was washed with CH₂Cl₂ (20 mL). The resultingsolid was collected and dried in vacuo to give 1.50 g ofN-(3-carbamoylthiophen-2-yl)nicotinamide as a brown solid (quantitativeyield). LCMS m/z=248.1 (M+1) (Method B) (retention time=1.34 min).

2-(Pyridin-3-yl)thieno[2,3-d]pyrimidin-4(3H)-one (iv-b)

A mixture of N-(3-carbamoylthiophen-2-yl)nicotinamide (1.50 g salt, 6.07mmol, 1.0 eq.) in EtOH (300 mL) was added NaOH (1.50 g, 37.5 mmol, 6.18eq.). The resulting mixture was stirred at 80° C. for 7 days. After thereaction was completed, the volatiles were removed in vacuo. Water (20mL) was added to the residue and the pH1 was adjusted to around 2 byadding dilute HCl (2N in water). The solution was concentrated in vacuoto give 11.0 g of the HCl salt as a beige solid. LCMS m/z=230.0 (M+1)(Method B) (retention time=1.21 min). The crude product containing saltswere used for the next step without further purification.

4-Chloro-2-(pyridin-3-yl)thieno[2,3-d]pyrimidine (v-c)

The suspension of 2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-4(3H)-one (6.0g, containing salts) in POCl₃ (30 ml.) was stirred at 120° C. for 10 h.After the reaction was completed, the mixture was added to ice-waterslowly. The pH was adjusted to ˜7 by slowly adding NH₃.H₂O at 0° C.,then a precipitate formed. The solid was collected and 540 mg of4-chloro-2-(pyridin-3-yl)thieno[2,3-d]pyrimidine was obtained as a brownsolid, LCMS m/z=247.9, 250.0 (M+1) (Method B) (retention time=1.85 min).

N-(3-Chloro-4-fluorophenyl)-2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-4-amine(vi-l)

A mixture of 4-chloro-2-(pyridin-3-yl)thieno[2,3-d]pyrimidine (80 mg,0.32 mmol, 1.0 eq.) and 3-chloro-4-fluorobenzenamine (93 mg, 0.64 mmol,2.0 eq.) in i-AmOH (8 mL) was stirred at 130° C. overnight. A yellowprecipitate formed and was collected and washed with MeOH (10 mL). Thesolid was suspended in H₂O (10 mL) and NH₃—H₂O (1 mL) was added. Afterfiltration and drying in vacuo, 23.0 mg of the product was obtained as ayellow solid (20.0%). LCMS m/z=357.0, 359.0 (M+1) (Method B) (retentiontime=1.96 min). ¹H-NMR (400 MHz, DMSO-d₆): δ 9.99 (s, 1H), 9.48 (d,J=1.6 Hz, 1H), 8.70-8.67 (m, 1H), 8.63 (d, J=8.0 Hz, 1H), 8.27 (dd,J=6.8, 2.6 Hz, 1H), 7.76-7.93 (m, 3H), 7.54-7.57 (m, 2H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 33, replacing 4-fluoro-3-chloroaniline withthe appropriate aniline.

TABLE 10 Molec- ¹H- Method Num- Salt ular NMR LCMS Purity for berPRODUCT type Mass ¹H-NMR Solvent LCMS Protocol percent Coupling 1012

347.39 1H-NMR (400 MHz, DMSO-d6): δ 12.69 (s, 1H), 9.55 (d, J = 1.3 Hz,1H), 9.00 (d, J = 8.0 Hz, 1H), 8.44 (s, 1H), 8.60-8.78 (m, 2H),7.82-8.00 (m, 3H), 7.42-7.79 (m, 3H), 7.20 (t, J = 7.2 Hz, 1H). DMSO348.1 (M + 1) Method B (NH4HCO3) 95 Method C, G3 1013

370.38 1H-NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1H), 9.51 (d, J = 1.2 Hz,1H), 8.60-8.77 (m, 2H), 7.98-7.94 (m, 2H), 7.71-7.86 (m, 2H), 7.56-7.50(m, 1H), 7.30 (t, J = 74.0 Hz, 1H), 6.96 (dd, J = 8.8, 2.0 Hz, 1H), DMSO371.0 (M + 1) Method B (NH4HCO3) 95 Method C, G3 1014

388.37 1H-NMR (400 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.50 (d, J = 1.6 Hz,1H), 8.58-8.75 (m, 2H), 8.18 (s, 1H), 7.77-8.00 (m, 3H), 7.50-7.65 (m,2H), 7.08-7.18 (m, 1H) DMSO 389.0 (M + 1) Method B (NH4HCO3) 95 MethodC, G3 1015

356.8  1H-NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 9.48 (d, J = 1.6 Hz,1H), 8.70-8.67 (m, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.27 (dd, J = 6.8, 2.6Hz, 1H), 7.76-7.93 (m, 3H), 7.54-7.57 (m, 2H). DMSO 357.0, 359.0 (M + 1)Method B (NH4HCO3) 95 Method C, G3

Method AA: 2-Amino-N-(cyclopropylmethyl)benzamide (ii-c)

A 100 ml, round bottom flask was charged with anthranilic acid (500 mg,3.65 mmol), added DMF (15 mL) under nitrogen atmosphere and stirring.Then, added N-methylmorpholine (1 mL, 9.12 mmol),aminomethylcyclopropane (311 mg, 4.38 mmol),N-ethyl-N′-dimethylaminopropylcarbodiimide (EDCI) (840 mg, 4.38 mmol)and HOBt (670 mg, 4.38 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with water andextracted with diethyl ether (50 mL×2). The organic extracts werecombined, washed with brine, dried over MgSO₄, filtered and concentratedto afford amorphous colorless 2-amino-N-(cyclopropylmethyl)benzamide(500 mg, 72% yield), which was checked by NMR and used for next stepwithout further purification. ¹H-NMR (Bruker 300 MHz, DMSO-d₆) δ0.20-1.01 (m, 4H), 1.01-1.04 (m, 1H), 3.06-3.11 (m, 2H), 6.37-8.21 (m,7H).

Method Z:2-(6-chloro-2-(pyridin-3-yl)quinazolin-4-ylamino)-N-(cyclopropylmethyl)benzamide(xiv-g)

A 100 mL round bottom flask was charged with4,6-dichloro-2-(pyridin-3-yl)quinazoline (synthesized as described inScheme 1 and 4, substituting 5-chloro-2-nitrobenzoic acid for2-nitro-5-propoxy-benzoic acid) (150 mg, 0.54 mmol) and2-amino-N-(cyclopropylmethyl)benzamide) (310 mg, 1.63 mmol) andanhydrous i-PrOH (20 mL) was added and refluxed for 3 h. The reactionmixture was cooled to room temperature and Et₃N (3 eq) was added. Thesolvent was removed in vacuo. To the crude product was added awater-methanol mixture (5:1, 50 mL), and then sonicated for 5 min. Thesolidified compound was collected by filtration, and the solid wasrecrystallized from hot methanol and washed with water. The product wasdried at 50° C. to give2-(6-chloro-2-(pyridin-3-yl)quinazolin-4-ylamino)-N-(cyclopropylmethyl)benzamideas a colorless cotton (220 mg, 94%). The structure was confirmed by NMRand elemental analysis. ¹H NMR (Bruker 300 MHz, DMSO-d₆) ppm 0.20-0.98(m, 5H), 3.07-3.21 (m, 2H), 7.24-8.26 (m, 7H), 8.68-9.55 (m, 5H), 12.22(s, 1H). CHN Calcd. C, 67.05; H, 4.69; N, 16.29. Found C, 67.15; H,4.89; N, 16.25

The compounds in the following table were prepared in a manner analogousto that described in Scheme 34, replacing aminomethylcyclopropane withthe appropriate amine.

TABLE 11 ¹H-NMR Purity Method of Number Product ¹H-NMR Solvent percentCoupling 1016

¹H NMR (DMSO-d₆) ppm 1.46 (d, 3H, J = 6.7 Hz), 3.90 (s, 3H), 5.17-5.22(m, 1H), 7.19-7.98 (m, 12H), 8.67-8.71 (m, 2H), 8.90 (d, 1H, J = 8.2Hz), 9.22 (d, 1H, J = 8.3 Hz), 9.55 (s, 1H), 12.18 (s, 1H). DMSO >93Method Z 1017

¹H NMR (DMSO-d₆) ppm 1.49- 1.62 (m, 8H), 3.99 (s, 3H), 4.24- 4.26 (m,1H), 7.24-7.71 (m, 7H), 8.65-9.55 (m, 5H), 12.19 (s, 1H). DMSO >98Method Z 1018

¹H NMR (DMSO-d₆) ppm 0.88- 1.99 (m, 7H), 3.14-3.16 (m, 2H), 3.02 (s,3H), 7.57-7.91 (m, 7H), 8.68-9.55 (m, 5H), 12.19 (s, 1H). DMSO >98Method Z 1019

¹H NMR (DMSO-d₆) ppm 1.07- 1.12 (m, 3H), 3.44-3.52 (m, 2H), 4.01 (s,3H), 7.24-786 (m, 8H), 8.68-9.55 (m, 5H), 12.19 (s, 1H). DMSO >98 MethodZ 1020

1H NMR (DMSO-d₆) ppm 0.87- 0.92 (m, 3H), 1.53-1.62 (m, 2H, ), 3.30-3.32(m, 2H), 3.98 (s, 3H), 7.21-7 89 (m 7H), 8.67-9.55 (m, 5H), 12.38 (s,1H). DMSO >98 Method Z 1021

1H NMR (DMSO-d₆) ppm 0.83- 1.51 (m, 7H), 3.30-3.32 (m, 2H), 3.99 (s,3H), 7.24-7.90 (m, 7H), 8.67-9.55 (m, 5H), 12.38 (s, 1H). DMSO >98Method Z 1022

1H NMR (DMSO-d₆) ppm 0.79- 1.52 (m, 9H), 3.25-3.30 (m, 2H), 3.98 (s,3H), 7.21-7.88 (m, 7H), 8.68-9.55 (m, 5H), 12.30 (s, 1H). DMSO >98Method Z 1023

1H NMR (DMSO-d₆) ppm 0.80- 1.49 (m, 11H), 3.26-3.30 (m, 2H), 3.99 (s,3H), 7.24-7.90 (m, 7H), 8.67-9.56 (m, 5H), 12.30 (s, 1H). DMSO >98Method Z 1024

1H NMR (DMSO-d₆) ppm 3.99- 4.10 (m, 5H), 5.07-5.33 (m, 2H), 5.89-5.91(m,1H), 7.24-7.90 (m, 7H), 8.68-9.55 (m, 5H), 12.30 (s, 1H). DMSO >98Method Z 1025

1H NMR (DMSO-d₆) ppm 3.13 (s, 1H), 3.99-4.12 (m, 5H), 7.21-7.89 (m, 7H),8.67-9.54 (m, 5H), 12.30 1H). DMSO >98 Method Z 1026

1H NMR (DMSO-d₆) ppm 1.68- 2.22 (m, 6H), 3.99 (s, 3H), 4.24- 4.26 (m,1H), 7.22-7.92 (m, 7H), 8.66-9.55 (m, 5H), 12.30 (s, 1H). DMSO >98Method Z 1027

1H NMR (DMSO-d₆) ppm 1.41- 1.86 (m, 12H), 3.90 (br s, 4H), 7.23-7.89 (m,7H), 8.63-9.55 (m, 5H), 12.30 (s, 1H). DMSO >98 Method Z 1028

1H NMR (DMSO-d₆) ppm 0.85- 1.60 (m, 9H), 3.27-3.33 (m, 2H), 3.99 (s,3H), 7.21-7.91 (m, 7H), 8.68-9.55 (m, 5H), 12.19 (s, 1H). DMSO >98Method Z 1029

1H NMR (DMSO-d₆) ppm 1.03- 1.34 (m, 6H), 3.17-3.31 (m, 4H), 7.40-7.88 (m7H), 8.55-10.03 (m, 5H), 12.32 (s, 1H). DMSO >98 Method Z 1030

1H NMR (DMSO-d₆) ppm 0.83- 1.52 (m, 5H), 3.20-3.29 (m, 2H), 7.27-8.21(m, 7H), 8.67-9.53 (m, 5H), 12.33 (s, 1H). DMSO >98 Method Z 1031

1H NMR (DMSO-d₆) ppm 1.02- 1.07 (m, 3H), 3.24-3.32 (m, 2H), 7.27-8.22(m, 7H), 8.67-9.53 (m, 5H), 12.34 (s, 1H). DMSO >98 Method Z 1032

1H NMR (DMSO-d₆) ppm 0.75- 1.37 (m, 7H), 3.18-3.20 (m, 2H) , 7.21-8.19(m, 7H), 8.64-9.48 (m, 5H), 12.15 (s, 1H). DMSO >98 Method Z 1033

1H NMR (DMSO-d₆) ppm 3.90- 3.92 (m, 2H), 5.02-5.17 (m, 2H), 5.81-5.86(m, 1H), 7.27-8.23 (m, 7H), 8.68-9.55 (m, 5H), 12.25 (s, 1H). DMSO >98Method Z 1034

1H NMR (DMSO-d₆) ppm 0.78- 1.42 (m, 11H), 3.20-3.29 (m, 2H), 7.25-7.91(m, 7H), 8.23-9.53 (m, 5H), 12.17 (s, 1H). DMSO >98 Method Z 1035

¹H NMR (DMSO-d₆) ppm 3.06 (s, 1H), 4.05-4.08 (m, 2H), 7.28-8.22 (m, 7H),8.65-9.51 (m, 5H), 12.12 (s, 1H). DMSO >98 Method Z 1036

1H NMR (DMSO-d₆) ppm 0.88- 1.92 (m, 7H), 3.05-3.16 (m, 2H), 7.23-7.94(m, 7H), 8.22-9.54 (m, 5H), 12.21 (s, 1H). DMSO >98 Method Z 1037

1H NMR (DMSO-d₆) ppm 1.37- 1.79 (m, 12H), 3.90-3.96 (m, 1H), 7.25-8.24(m, 7H), 8.55-9.52 (m, 5H), 12.07 (s, 1H). DMSO >98 Method Z 1038

1H NMR (DMSO-d₆) ppm 1.49- 1.85 (m, 8H), 4.24-4.26 (m, 1H), 7.23-7.69(m, 6H), 7.85-9.53 (m, 6H), 12.06 (s, 1H). DMSO >98 Method Z 1039

1H NMR (DMSO-d₆) ppm 1.12- 1.14 (m, 6H), 4.11-4.18 (m, 1H), 7.23-7.94(m, 8H), 8.33-9.53 (m, 4H), 12.30 (s, 1H). DMSO >98 Method Z 1040

1H NMR (DMSO-d₆) ppm 0.84- 1.16 (m, 9H), 3.28-3.34 (m, 2H), 7.23-7.91(m, 6H), 8.25-9.53 (m, 6H), 12.16 (s, 1H). DMSO >98 Method Z 1041

1H NMR (DMSO-d₆) ppm 0.79- 1.52 (m, 9H), 3.25-3.32 (m, 2H), 7.24-7.91(m, 6H), 8.23-9.53 (m, 6H), 12.18 (s, 1H). DMSO >98 Method Z 1042

1H NMR (DMSO-d₆) ppm 1.04- 1.81 (m, 10H), 3.77-3.82 (m, 1H), 7.21-8.05(m, 8H), 8.65-9.52 (m, 4H), 11.96 (s, 1H). DMSO >98 Method Z 1043

1H NMR (DMSO-d₆) ppm 0.47- 0.67 (m, 4H), 2.85-2.88 (m, 1H), 7.26-8.26(m, 7H), 8.66-9.52 (m, 5H), 12.26 (s, 1H). DMSO >98 Method Z 1044

1H NMR (DMSO-d₆) ppm 1.14 (s, 9H), 7.30-7.93 (m, 7H), 8.21- 9.50 (m,5H), 12.22 (s, 1H). DMSO >98 Method Z 1045

1H NMR (DMSO-d₆) ppm 3.98 (s, 3H), 4.36 (s, 2H), 6.47 (s, 1H), 7.21-7.91(m, 9H), 8.68-9.56 (m, 5H), 12.22 (s, 1H). DMSO >98 Method Z 1046

1H NMR (DMSO-d₆) ppm 4.30 (s, 2H), 6.42 (s, 1H), 7.28-8.24 (m, 9H),8.70-9.53 (m, 5H), 12.22 (s, 1H). DMSO >98 Method Z 1047

1H NMR (DMSO-d₆) ppm 1.69- 2.55 (m, 6H), 4.41-4.44 (m, 1H), 7.23-8.24(m, 7H), 8.65-9.54 (m, 5H), 12.06 (s, 1H). DMSO >98 Method Z 1048

1H NMR (DMSO-d₆) ppm 4.55 (s, 2H), 7.17-8.21 (m, 12H), 8.65- 9.54 (m,5H), 12.06 (s, 1H). DMSO >98 Method Z 1049

1H NMR (DMSO-d₆) ppm 7.02- 8.67 (m, 15H), 9.47 (s, 1H), 10.04 (s, 1H),12.06 (s, 1H). DMSO >98 Method Z 1050

1H NMR (DMSO-d₆) ppm 2.75- 2.80 (m, 2H), 3.48-3.54 (m, 2H), 7.08-8.20(m, 12H) 8.69-9.56 (m, 5H), 12.16 (s, 1H). DMSO >98 Method Z 1051

1H NMR (DMSO-d₆) ppm 4.01- 4.10 (m, 2H), 7.28-8.27 (m, 7H), 8.59-9.51(m, 5H), 11.45 (s, 1H). DMSO >98 Method Z 1052

1H NMR (DMSO-d₆) ppm 4.38- 4.57 (m, 4H), 7.27-8.24 (m, 7H), 8.69-9.56(m, 5H), 12.10 (s, 1H). DMSO >98 Method Z 1053

1H NMR (DMSO-d₆) ppm 2.85- 2.92 (br s, 3H), 7.20-8.22 (m, 7H), 8.67-9.56(m, 5H), 12.61 (s, 1H). DMSO >98 Method Z 1054

1H NMR (DMSO-d₆) ppm 1.04- 1.81 (m, 10H), 3.77-3.82 (m, 1H), 7.24-8.05(m, 8H), 8.65-9.52 (m, 4H), 12.27 (s, 1H). DMSO >98 Method Z 1055

1H NMR (DMSO-d₆) ppm 2.49- 2.51 (m, 2H), 3.57-3.59 (m, 2H), 7.21-8.16(m, 12H), 8.69-9.56 (m, 5H), 12.16 (s, 1H). DMSO >98 Method Z 1056

1H NMR (DMSO-d₆) ppm 0.79- 1.44 (m, 11H), 3.26-3.30 (m, 2H), 7.24-7.92(m, 7H), 8.67-9.52 (m, 5H), 12.45 (s, 1H). DMSO >98 Method Z 1057

1H NMR (DMSO-d₆) ppm 1.04- 1.16 (m, 3H), 3.33-3.38 (m, 2H), 7.20-8.22(m, 7H), 8.60-9.53 (m, 5H), 12.34 (s, 1H). DMSO >98 Method Z 1058

1H NMR (DMSO-d₆) ppm 7.09- 8.68 (m, 15H), 9.51 (s, 1H), 10.34 (s, 1H),12.06 (s, 1H). DMSO >98 Method Z 1059

1H NMR (DMSO-d₆) ppm 3.78 (s, 3H), 4.43 (s, 2H), 6.77-8.23 (m, 11H),8.68-9.54 (m, 5H), 12.06 (s, 1H). DMSO >98 Method Z 1060

1H NMR (DMSO-d₆) ppm 3.69 (s, 3H), 4.48 (s, 2H), 6.89-8.15 (m, 11H),8.68-9.54 (m, 5H), 12.44 (s, 1H). DMSO >98 Method Z 1061

1H NMR (DMSO-d₆) ppm 2.24 (s, 3H), 4.46 (s, 2H), 7.03-8.13 (m, 11H),8.67-9.54 (m, 5H), 12.21 (s, 1H). DMSO >98 Method Z 1062

1H NMR (DMSO-d₆) ppm 4.51 (s, 2H), 7.11-8.14 (m, 11H), 8.67- 9.54 (m,5H), 12.34 (s, 1H). DMSO >98 Method Z 1063

1H NMR (DMSO-d₆) ppm 4.47 (s, 2H), 7.05-8.14 (m, 11H), 8.67- 9.54 (m,5H), 12.37 (s, 1H). DMSO >98 Method Z 1064

1H NMR (DMSO-d₆) ppm 3.95 (s, 3H), 4.47 (s, 2H), 7.05-8.14 (m, 11H),8.67-9.54 (m, 5H), 12.32 (s, 1H). DMSO >98 Method Z Meth- Pur- od ¹H ityof Num- Starting Starting Salt NMR per- Coup- ber Material R¹ MaterialR³ Product Type ¹H NMR Solvent cent ling 1065

¹H NMR (DMSO-d₆) ppm 4.52 (d, 2H, J = 5.8 Hz), 7.21-7.30 (m, 5H), 7.50(t, J = 7.9 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.89- 7.92 (m, 3H), 8.21(d, J = 1.8 Hz, 1H), 8.65- 8.70 (m, 3H), 8.99 (s, 1H), 9.52 (s, 1H),11.88 (s, 1H) DMSO >98 Meth- od Y, Z 1066

¹H NMR (DMSO-d₆) ppm 4.49 (d, 2H, J = 5.6 Hz), 7.24-7.35 (m, 5H), 7.50(t, J = 7.2 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.91- 7.95 (m, 3H), 8.22(d, J = 1.5 Hz, 1H), 8.67- 8.73 (m, 3H), 9.19 (s, 1H), 9.53 (s, 1H),11.98 (s, 1H) DMSO >98 Meth- od Y, Z 1067

¹H NMR (DMSO-d₆) ppm 4.58 (d, 2H, J = 5.7 Hz), 7.16-7.36 (m, 5H), 7.50(t, J = 7.5 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.88- 7.96 (m, 3H), 8.22(d, J = 1.5 Hz, 1H), 8.65- 8.69 (m, 3H), 8.98 (s, 1H), 9.52 (s, 1H),11.87 (s, 1H) DMSO >98 Meth- od Y, Z 1068

¹H NMR (DMSO-d₆) ppm 4.47 (d, 2H, J = 5.6 Hz), 7.30 (br s, 5H), 7.54 (t,J = 7.7 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.88- 7.96 (m, 3H), 8.15 (d,J = 1.5 Hz, 1H), 8.68-8.81 (m, 3H), 8.98 (s, 1H), 9.52 (s, 1H), 12.29(s, 1H) DMSO >98 Meth- od Y, Z 1069

¹H NMR (DMSO-d₆) ppm 4.57 (d, 2H, J = 5.6 Hz), 7.23-7.29 (m, 5H), 7.39(t, J = 7.9 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.94- 7.99 (m, 3H), 8.15(d, J = 1.4 Hz, 1H), 8.68- 8.84 (m, 3H), 9.24 (s, 1H), 9.55 (s, 1H),12.23 (s, 1H) DMSO >98 Meth- od Y, Z 1070

¹H NMR (DMSO-d₆) ppm 4.50 (d, 2H, J = 5.5 Hz), 7.25-7.53 (m, 5H), 7.69(t, J = 7.1 Hz, 1H), 7.73 (t, J = 7.0 Hz, 1H), 7.94- 8.15 (m, 3H), 8.18(d, J = 1.4 Hz, 1H), 8.68- 8.82 (m, 3H), 9.24 (s, 1H), 9.54 (s, 1H),12.21 (s, 1H) DMSO >98 Meth- od Y, Z 1071

¹H NMR (DMSO-d₆) ppm 3.90 (s, 3H), 4.56 (d, 2H, J = 5.6 Hz), 7.22-7.44(m, 7H), 7.44 (t, J = 7.9 Hz, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.94- 7.99(m, 2H), 8.68- 8.81 (m, 3H), 9.24 (s, 1H), 9.55 (s, 1H), 12.19 (s,1H)DMSO >98 Meth- od Y, Z 1072

HCl ¹H NMR (400 MHz, DMSO-d₆): δ 12.17 (s, 1H), 9.52 (s, 1H), 9.08 (s,1H), 8.95 (d, J = 7.6 Hz, 1H), 8.85 (s, 1H), 8.66 (d, J = 7.8 Hz, 1H),7.91 (t, J = 9.4 Hz, 2H), 7.84 (s, 1H), 7.75-7.67 (m, 1H), 7.65 (s, 1H),7.59 (d, J = 8.1 Hz, 1H), 7.30 (t, J = 7.3 Hz, 1H), 4.47 (d, J = 47.3Hz, 2H), 4.26 (d, J = 6.8 Hz, 2H), 3.58-3.50 (m, 2H), 1.47 (t, J = 6.7Hz, 3H). DMSO   95 Meth- od Y, Z

Method AB: Methyl 3-(4-hydroxy-2-(pyridin-3-yl)quinazolin-6-yl)acrylate(xxvi-a)

To a solution of 6-iodo-2-(pyridin-3-yl) quinazolin-4-ol (synthesized asdescribed in Scheme 1 and 4, substituting 5-iodo-2-nitrobenzoic acid for2-nitro-5-propoxy-benzoic acid) (3.00 g, 8.6 mmol, 1.0 eq.), Pd(OAc)₂(48 mg, 0.21 mmol, 0.025 eq.) and PPh₃ (113 mg, 0.43 mmol, 0.05 eq.) inDMF (8 mL) was added methyl acrylate (3.22 g, 25.8 mmol, 3.0 eq.) andDIPEA (1.22 g, 9.46 mmol, 1.1 eq.) under Ar atmosphere. The mixture wasstirred at 110° C. overnight. After cooling, the mixture was filteredand the solid was washed with ethyl acetate three times to afford 1.30 gof xxxvi-a as green solid (yield 49%). LCMS m/z=308.0 (M+1) (Method B)(retention time=1.41 min).

Methyl 3-(4-hydroxy-2-(pyridin-3-yl)quinazolin-6-yl)propanoate (xxvii-a)

Methyl 3-(4-hydroxy-2-(pyridin-3-yl)quinazolin-6-yl)propanoate wasprepared in a manner analogous to that described for2-amino-5-methoxybenzoic acid in Method K, replacing5-methoxy-2-nitrobenzoic acid with methyl3-(4-hydroxy-2-(pyridin-3-yl)quinazolin-6-yl)acrylate to afford 1.40 gof xxvii-a in quantitative yield as a yellow solid. LCMS m/z=310.0 (M+1)(Method B) (retention time=1.42 min).

3-(4-Chloro-2-pyridin-3-yl-quinazolin-6-yl)-propionic acid methyl ester(xxviii-a)

3-(4-Chloro-2-pyridin-3-yl-quinazolin-6-yl)-propionic acid methyl ester(prepared in a manner analogous to that described for4-chloro-6-propoxy-2-pyridin-3-yl-quinazoline using Method F, replacing6-propoxy-2-pyridin-3-yl-1H-quinazolin-4-one with methyl3-(4-hydroxy-2-(pyridin-3-yl)quinazolin-6-yl)propanoate) was obtained inquantitative yield to give 1.50 g of xxvii-a as a red solid. LCMSm/z=328.1, 330.0 (M+1) (Method B) (retention time=1.86 min).

3-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-propionicacid methyl ester (xxviv-a)

3-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-propionicacid methyl ester (prepared in a manner analogous to that described for2-(6-propoxy-2-pyridin-3-yl-quinazolin-4-ylamino)-benzamide in MethodG1, replacing 4,7-dichloro-2-(4-chlorophenyl)quinazoline and2-aminobenzamide with3-(4-chloro-2-pyridin-3-yl-quinazolin-6-yl)-propionic acid methyl esterand 3-chloro-4-fluoro-phenylamine) was obtained in a 43% yield to give1.04 g of xxviv-a as a yellow solid. LCMS m/z=437.1, 439.1 (M+1) (MethodB) (retention time=1.62 min).

Method AC: 3-(4-(3-Chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propanoic acid (xxx-a)

To a solution of3-[4-(3-chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-propionicacid methyl ester (1.04 g, 2.39 mmol, 1.0 eq.) in DMF (20 mL) was addeda solution of NaOH (0.57 g, 14.3 mmol, 6.0 eq.) in H₂O (8 mL). Themixture was stirred at room temperature for 2 h. 50 mL of water wasadded to the mixture. After filtration, the resulting filter cake waswashed with water and dried in vacuo to give 933 mg of xxx-a as a yellowsolid (yield 93%). LCMS m/z=423.1, 425.1 (M+1) (Method A) (retentiontime=1.51 min).

3-(4-(3-Chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)-N,N-dimethylpropanamide (xxxi-a)

3-(4-(3-Chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)-N,N-dimethylpropanamide (prepared in a manner analogous to that described for2-benzamido-5-methoxy-3-methylbenzamide in Method D, replacing nicotinicacid and 2-amino-5-methoxy-3-methylbenzamide with3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propanoicacid and dimethylamine hydrochloride) was obtained in 90% yield to give891 mg of xxxi-a as a yellow solid. LCMS m/z=450.0, 452.0 (M+1) (MethodB) (retention time=1.834 min). ¹H-NMR (400 MHz, DMSO-d₆): δ 9.95 (s,1H), 9.51 (d, J=1.6 Hz, 1H), 8.69-8.63 (m, 2H), 8.38 (s, 1H), 8.28 (dd,J=6.8, 2.4 Hz, 1H), 7.94-7.90 (m, 1H), 7.81 (s, 2H), 7.55-7.51 (m, 2H),3.04 (t, J=7.6 Hz, 2H), 2.99 (s, 3H), 2.85 (s, 3H), 2.77 (t, J=8.0 Hz,2H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 36, replacing dimethylamine with theappropriate amine and 4-fluoro, 3-chloro aniline with the appropriateaniline.

TABLE 12 Salt Molecular ¹H-NMR LCMS Purity Method for Number PRODUCTtype Mass ¹H-NMR Solvent LCMS Protocol percent Coupling 1073

421.85 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.01 (s, 1H), 9.52 (s, 1H),8.65-8.69 (m, 2H), 8.39 (s, 1H), 8.28 (d, J = 5.2 Hz, 1H), 7.92-7.93 (m,1H), 7.82 (q, J = 8.0 Hz, 2H), 7.52-7.57 (m, 2H), 7.35 (s, 1H), 6.84 (s,1H), 3.05 (t, J = 7.2 Hz, 2H), 2.51-2.54 (m, 2H). DMSO 422.1 (M + 1)Method B (NH4HCO3) 95 Method C 1074

435.43 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.01 (s, 1H), 9.55 (d, J = 2.4 Hz,1H), 8.68-8.70 (m, 2H), 8.47 (s, 1H), 7.97-7.99 (m, 1H), 7.79-7.36 (m,3H), 7.50- 7.55 (m, 2H), 7.36 (s, 1H), 7.30 (t, J = 73.6 Hz, 1H), 6.99(dd, J = 8.4, 2.4 Hz, 1H), 6.82 (s, 1H), 3.05 (t, J = 8.0 Hz, 2H), 2.52(t, J = 8.4 Hz, 2H). DMSO 436.2 (M + 1) Method B (NH4HCO3) 95 Method C1075

435.88 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.00 (s, 1H), 9.52 (s, 1H),8.65-8.69 (m, 2H), 8.39 (s, 1H), 8.27- 8.29 (m, 1H), 7.79 (dd, J = 9.2,2.4 Hz, 1H), 7.76- 7.85 (m, 3H), 7.52-7.57 (m, 2H), 3.05 (t, J = 7.6 Hz,2H), 2.57 (d, J = 4.4 Hz, 3H), 2.52-2.54 (m, 2H). DMSO 436.1 (M + 1)Method B (NH4HCO3) 95 Method D 1076

449.91 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.95 (s, 1H), 9.51 (d, J = 1.6 Hz,1H), 8.63-8.59 (m, 2H), 8.38 (s, 1H), 8.28 (dd, J = 6.8, 2.4 Hz, 1H),7.90-7.94 (m, 1H), 7.81 (s, 2H), 7.51-7.55 (m, 2H), 3.04 (t, J = 7.6 Hz,2H), 2.99 (s, 3H), 2.35 (s, 3H), 2.77 (t, J = 8.0 Hz, 2H). DMSO 450.0(M + 1) Method B (NH4HCO3) 95 Method D 1077

540.01 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.01 (s, 1H), 9.52 (d, J = 1.6 Hz,1H), 8.61-8.74 (m, 2H), 8.41 (s, 1H), 8.28 (dd, J = 6.8, 2.6 Hz, 1H),7.80-7.99 (m, 3H), 7.46-7.63 (m, 2H), 3.89 (s, 4H), 3.20 (s, 2H), 3.08(t, J = 7.4 Hz, 4H), 2.90 (t, J = 7.6 Hz, 2H). DMSO 540.2, 542.2 (M + 1)Method B (NH4HCO3) 95 Method D

(E)-4-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-but-3-enenitrile(xxxii-a)

(E)-4-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-but-3-enenitrile(prepared in a manner analogous to that described for (E)-methyl3-(4-hydroxy-2-(pyridin-3-yl)quinazolin-6-yl)acrylate using Method AB,replacing 6-iodo-2-(pyridin-3-yl)quinazolin-4-ol and methyl acrylatewithN-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amineand but-3-enenitrile) was obtained in a 48% yield to give 400 mg ofxxii-a as grey solid. LCMS m/z=416.0 (M+1) (Method B) (retentiontime=1.99 min).

4-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-butyronitrile(xxxiii-a)

4-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-butyronitrile(prepared in a manner analogous to that described for2-amino-5-methoxybenzoic acid in Method K, replacing5-methoxy-2-nitrobenzoic acid with(E)-4-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)but-3-enenitrile)was obtained in a 95% yield to give 190 mg of xxxiii-a as a brown solid.LCMS m/z=418.1 (M+1) (Method B) (retention time=1.95 min).

Method AD:4-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)butanoicacid (xxxiv-a)

4-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-butyronitrile(190 mg, 046 mmol, 1.0 eq.) was treated with concentrated HCl (8 mL).The mixture was stirred at 100° C. for 2 days. The volatiles wereremoved in vacuo, and the residue was washed with water to afford 70 mgof xxxiv-a in a 35% yield as a yellow solid. LCMS m/z=437.1, 439.1 (M+1)(Method B) (retention time=1.46 min).

4-(4-(3-Chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)-1-morpholinobutan-1-one (xxxv-a)

4-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)-1-morpholinobutan-1-one was prepared in a manneranalogous to that described for 2-benzamido-5-methoxy-3-methylbenzamidein Method D, replacing nicotinic acid and2-amino-5-methoxy-3-methylbenzamide with4-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)butanoic acid and morpholine to give 32 mg of xxxv-a in a 40% yield as abeige solid. LCMS m/z=506.2, 508.1 (M+1) (Method 1) (retention time=1.85min). ¹H NMR (400 MHz, DMSO-d₆): δ 10.04 (s, 1H), 9.52 (d, J=1.6 Hz,1H), 8.69-8.65 (m, 2H), 8.39-8.38 (m, 1H), 8.27 (dd, J=6.8, 2.8 Hz, 1H),7.94-7.90 (m, 1H), 7.86-7.84 (m, 1H), 7.80-7.77 (m, 1H), 7.57-7.52 (m,2H), 3.56-3.53 (m, 4H), 3.46-3.41 (m, 4H), 2.85 (t, J=8.0 Hz, 2H), 2.40(t, J=7.6 Hz, 2H), 1.97 (t, J=7.6 Hz, 2H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 38 in the synthesis of4-(4-(3-Chloro-4-fluorophenyl amino)-2-(pyridin-3-yl)quinazolin-6-yl)-1-morpholino butan-1-one, replacing(E)-4-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-but-3-enenitrilewith4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazoline-6-carbonitrile.

TABLE 13 Num- Salt Molecular ¹H-NMR LCMS Purity Method for ber PRODUCTtype Mass ¹H-NMR Solvent LCMS Protocol percent Coupling 1078

411.46 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.64 (d, J = 1.6 Hz, 1H), 8.78 (td,J = 7.9, 1.8 Hz, 1H), 8.71 (dd, J = 4.7, 1.6 Hz, 1H), 7.94 (d, J = 9.2Hz, 1H), 7.59 (brs, 1H), 7.58 (dd. J = 7.6, 4.8 Hz, 1H). 7.52 (dd, J =9.2. 2.8 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 6.4 Hz, 1H),6.84 (dd, J = 8.0, 1.1 Hz, 1H), 6.69 (s, 1H), 4.36 (t, J = 6.5 Hz, 2H),4.09 (t, J = 6.4 Hz, 2H), 3.46 (s, 3H), 2.30 (s, 3H). DMSO 412.2 (M + 1)Method B (NH4HCO3) 95 Method C, G 1079

506.96 ¹H NMR (400 MHz, DMSO-d₆): δ 10.42 (s, 1H), 9.54 (d, J = 1.6 Hz,1H), 9.08 (d, J = 1.2 Hz, 1H), 8.73- 8.65 (m, 3H), 8.28 (dd, J = 6.8,2.4 Hz, 1H), 7.97- 7.93 (m, 2H), 7.60-7.53 (m, 2H), 3.60-3.58 (m, 4H),3.51-3.46 (m, 2H), 2.55-2.53 (m, 2H), 2.41- 2.48 (m, 4H), DMSO 508.1(M + 1) 254.1 254.9 (M/2 + 1) Method B (NH4HCO3) 95 Method C, G, C 1080

461.92 ¹H NMR (400 MHz, DMSO-d₆): δ 10.21 (s, 1H), 9.54 (d, J = 1.6 Hz,1H), 8.72-8.67 (m, 2H), 8.64 (d, J = 1.2 Hz, 1H), 8.28 (dd, J = 7.0, 2.6Hz, 1H), 7.95- 7.86 (m, 3H), 7.60-7.53 (m, 2H), 3.68 (d, J = 2.4 Hz,2H), 3.37-3.34 (m, 2H), 1.65-1.51 (m, 6H). DMSO 462.0 464.0 (M + 1)232.3 (M/2 + 1) Method A (TFA) 95 Method C, G, C 1081

479.96 ¹H NMR (400 MHz, DMSO-d₆): δ 10.20 (s, 1H), 9.53 (d, J = 1.6 Hz,1H), 8.72-8.67 (m, 2H), 8.54 (d, J = 1.2 Hz, 1H), 8.28 (dd, J = 6.8, 2.8Hz, 1H), 7.97- 7.90 (m, 3H), 7.60-7.54 (m, 2H), 3.97-3.94 (m, 2H),3.66-3.60 (m, 2H), 2.77-2.67 (m, 4H). DMSO 480.0 482.0 (M + 1) 240.6(M/2 + 1) Method A (TFA) 95 Method C, G, C 1082

421.85 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.20 (s, 1H), 9.55 (d, J = 1.6 Hz,1H), 8.79-8.64 (m, 3H), 8.29 (dd, J = 6.8, 2.6 Hz, 1H), 8.01-7.87 (m,3H), 7.53-7 .60 (m, 2H), 3.15-3.05 (m, 3H), 3.02 (s, 3H). DMSO 422.1,424.1 (M + 1) Method B (NH₄HCO₃) 95 Method C, G, D 1083

463.89 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.22 (s, 1H), 9.55 (d, J = 1.4 Hz,1H), 8.77-8.65 (m, 3H), 8.02-7 .87 (m, 3H), 7.60-7.54 (m, 2H), 3.56-3.39(m, 2H), 3.82-3.55 (m, 6H). DMSO 464.1, 466.1 (M + 1) Method B (NH₄HCO₃)95 Method C, G, D 1084

407.83 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.41 (s, 1H), 9.54 (d, J = 1.5 Hz,1H), 9.08 (d, J = 1.3 Hz, 1H), 8.76- 8.63 (m, 3H), 8.32-8.20 (m, 2H),7.96-7.93 (m, 2H), 7.63-7.50 (m, 2H), 2.88 (d, J = 4.5 Hz, 3H). DMSO408.0, 410.0 (M + 1) Method B (NH₄HCO₃) 95 Method C, G, D 1085

447.89 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.23 (s, 1H), 9.55 (d, J = 1.5 Hz,1H), 8.68-8.77 (m, 3H), 8.28 (dd, J = 6.9, 2.6 Hz, 1H), 8.02 (dd, J =8.6, 1.6 Hz, 1H), 7.99-7.90 (m, 2H), 7.53-7.58 (m, 2H), 3.57 (t, J = 6.8Hz, 2H), 3.51 (t, J = 6.4 Hz, 2H), 1.85-1.95 (m, 4H). DMSO 448.1, 420.1(M + 1) Method B (NH₄HCO₃) 95 Method C, G, D 1086

476.93 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.22 (s, 1H), 9.54 (d, J = 1.5 Hz,1H), 8.75-8.63 (m, 3H), 8.29 (dd, J = 6.8, 2.6 Hz, 1H), 8.01-7.84 (m,3H), 7.60-7.53 (m, 2H), 3.72 (d, J = 2.2 Hz, 2H), 3.51-3.39 (m, 2H),2.48-2.40 (m, 2H), 2.33 (d, J = 1.3 Hz, 2H), 2.24 (s, 3H). DMSO 477.1,479.1 (M + 1) 239.1, 239.9 (M/2 + 1) Method B (NH₄HCO₃) 95 Method C, G,D 1087

511.96 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.19 (s, 1H), 9.53 (d, J = 1.6 Hz,1H), 8.59-8.82 (m, 3H), 8.26 (dd, J = 6.8, 2.6 Hz, 1H), 7.81-8.14 (m,3H), 7.57 (m, 2H), 3.83-4.10 (m, ,4H), 3.33-3.35 (m, 4H). DMSO 512.1,514.1 (M + 1) Method B (NH4HCO3) 95 Method C, G, D 1088

481.91 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.47 (s, 1H), 9.54 (d, J = 1.6 Hz,1H), 9.23 (d, J = 1.2 Hz, 1H), 8.72- 8.74 (m, 3H), 8.22-8.42 (m, 2H),7.85-8.12 (m, 2H), 7.55-7.59 (m, 2H), 4.61 (t, J = 5.4 Hz, 1H), 3.47 (t,J = 5.2 Hz, 2H), 3.37 (s, 6H), DMSO 482.1, 484.2 (M + 1) Method B(NH4HCO3) 95 Method C, G, D 1089

421.85 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.23 (s, 1H), 9.59 (d, J = 1.2 Hz,1H), 8.72-8.77 (m, 2H), 8.68 (d, J = 8.4 Hz, 1H), 8.34 (dd, J = 7.2, 2.0Hz, 1H), 7.96- 8.00 (m, 1H), 7.92 (m, 1H), 7.72-7.74 (m, 1H), 7.58-7.65(m, 2H), 3.13 (s, 3H), 3.03 (s, 3H). DMSO 422.0 (M + 1) Method A (TFA)95 Method C, G, D 1090

394.79 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.25 (s, 1H), 9.54 (s, 1H),8.68-8.70 (m, 2H), 8.60 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.32 (dd, J =7.2, 2.8 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.93-7.97 (m, 1H), 7.51-7.58 (m, 2H). DMSO 395.0 (M + 1) Method A (TFA) 95 Method C, G, D 1091

476.93 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.19 (s, 1H), 9.53 (s, 1H),8.62-8.72 (m, 3H), 8.29 (dd, J = 6.8, 2.4 Hz, 1H), 7.91-7.94 (m, 1H),7.83 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.53-7.59 (m, 2H), 3.69-3.71 (s,2H), 3.36-3.38 (s, 2H), 2.42-2.44 (s, 2H), 2.30- 2.32 (s, 2H), 2.23 (s,3H). DMSO 477.2 (M + 1) 239.1 (1/2M +1) Method B (NH4HCO3) 95 Method C,G, D 1092

463.89 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.18 (s, 1H), 9.52 (s, 1H),8.H)-8.71 (m, 3H), 8.28 (d, J = 4.8 Hz, 1H), 7.87-7.96 (m, 2H), 7.68 (d,J = 8.0 Hz, 1H), 7.52-7.58 (m, 2H), 3.61-3.71 (m, 6H), 3.40 (m, 2H).DMSO 464.1 (M + 1) Method B (NH4HCO3) 95 Method G, D 1093

393.8 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.20 (s, 1H), 9.54 (d, J = 1.6 Hz,1H), 8.62-8.72 (m, 3H), 8.42 (d, J = 1.2 Hz, 1H), 8.37 (s, 1H), 8.30(dd, J = 7.2, 2.8 Hz, 1H), 8.08 (dd, J = 8.4, 1.2 Hz, 1H), 7.91-7.95 (m,1H), 7.71 (s, 1H), 7.53-7.60 (m, 2H). DMSO 394.1 (M + 1) Method B(NH4HCO3) 95 Method G, D 1094

407.83 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.19 (s, 1H), 9.53 (s, 1H), 8.84(d, J = 4.0 Hz, 1H), 8.60-8.72 (m, 3H), 8.35 (s, 1H), 8.29 (dd, J = 6.8,2.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.90-7.93 (m, 1H), 7.52- 7.59 (m,2H), 2.87 (d, J = 4.8 Hz, 3H). DMSO 408.1 (M + 1) Method B (NH4HCO3) 95Method G, D 1095

HCl 506.96 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.20 (s, 1H), 9.53 (d, J = 1.6Hz, 1H), 8.85 (t, J = 5.6 Hz, 1H), 8.61- 8.72 (m, 3H), 8.36 (d, J = 1.2Hz, 1H), 7.93 (dd, J = 6.4, 2.4 Hz, 1H), 8.03 (dd, J = 8.8, 1.6 Hz, 1H),7.91- 7.95 (m, 1H), 7.52-7.59 (m, 2H), 3.60 (t, J = 4.4 Hz, 4H),3.46-3.48 (q, J = 6.4 Hz, 2H), 2.51-2.54 (m, 2H), 2.42-2.48 (m, 4H).DMSO 507.1 (M + 1) 254.1 (M/2 +1) Method B (NH4HCO3) 95 Method G, C 1096

511.96 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.22 (s, 1H), 9.56 (d, J = 1.8 Hz,1H), 8.61-8.79 (m, 3H), 8.31 (dd, J = 6.8, 2.6 Hz, 1H), 7.88-8.11 (m,2H), 7.78 (dd, J = 8.4, 1.4 Hz, 1H), 7.51-7.66 (m, 2H), 4.12 (brs, 2H),3.76 (brs, 2H), 3.30-3.33 (m, 4H). DMSO 512.1, 514.2 (M + 1) Method B(NH4HCO3) 95 Method G, D 1097

474 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.64 (brs, 1H), 9.53 (s, 1H), 9.44 (t,J = 6.4 Hz, 1H), 9.35 (s, 1H), 8.90 (d, J = 8.0 Hz, 1H), 8.85 (d, J =4.8 Hz, 1H), 8.35 (dd, J = 8.4, 1.2 Hz, 1H), 8.27 (dd, J = 6.8, 2.4 Hz,1H), 8.00-7.97 (m, 2H), 7.82 (dt, J = 13.2, 5.2 Hz, 1H), 7.55 (t, J =8.8 Hz, 1H), 4.22-4.18 (m, 2H). DMSO 475.7, 476.6 (M + 1) Method B(NH4HCO3) 95 Method C, G, D

Method AE:2-(7-(Methylamino)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide(xxxvi-a)

A mixture of 2-(7-amino-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide(160 mg, 0.449 mmol, 1.0 eq.) and HCHO (40%, 37 mg, 0.494 mmol, 1.1eq.), acetic acid (2 drops) were stirred at room temperature for 0.5 h.NaBH₃CN (34 mg, 0.449 mmol, 1.0 eq.) was added and the mixture wasstirred at room temperature overnight. After filtration, the filtratewas concentrated to give the crude product, which was purified byreverse phase chromatography (MeOH/H₂O=3:7) to afford 28 mg of xxxvi-aas a white solid (17%). LCMS m/z=371.1 (M+1), 372.1 (M+2) (Method B)(retention time=1.60 min). ¹H NMR (400 MHz, DMSO-d₆): δ 12.71 (s, 1H),9.58 (d, J=1.6 Hz, 1H), 9.14-9.12 (m, 1H), 8.74-8.69 (m, 2H), 8.45 (s,1H), 7.93-7.91 (m, 1H), 7.85 (d, J=9.2 Hz, 2H), 7.67-7.71 (m, 1H),7.59-7.55 (m, 1H), 7.12-7.16 (m, 1H), 7.06-7.03 (m, 1H), 6.82-6.81 (m,1H), 6.70 (d, J=2.4 Hz, 1H), 2.84 (d, J=4.8 Hz, 3H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 41, replacing formaldehyde with theappropriate aldehyde and 2-aminobenzamide with the appropriate aniline.

TABLE 14 Molec- ¹H- Purity Method Num- Salt ular NMR LCMS per- for berPRODUCT type Mass ¹H-NMR Solvent LCMS Protocol cent Coupling 1098

370.41 ¹H-NMR (400 MHz, DMSO-d₆): δ 12.87 (s, 1H), 9.57 (d, J = 1.2 Hz,1H), 9.25 (d, J = 8.8 Hz, 1H), 8.65- 8.71 (m, 2H), 8.47 (s, 1H),7.95-7.99 (m, 2H), 7.69-7.74 (m, 2H), 7.56 (dd, J = 7.7, 5.0 Hz, 1H),7.33 (dd, J = 9.1, 1.9 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 6.90 (d, J =1.2 Hz, 1H), 6.62 (d, J = 4.8 Hz, 1H), 2.88 (d, J = 4.8 Hz, 3H). DMSO371.1 (M + 1) Method B (NH₄HCO₃) 95 Method AE 1099

370.41 ¹H-NMR (400 MHz, DMSO-d₆): δ 12.71 (s, 1H), 9.58 (d, J = 1.4 Hz,1H), 9.13 (d, J = 7.7 Hz, 1H), 8.80- 8.64 (m, 2H), 8.45 (s, 1H), 7.92(dd, J = 7.9, 1.4 Hz, 1H), 7.85 (d, J = 9.2 Hz, 2H), 7.76-7.62 (m, 1H),7.57 (dd, J = 7.9, 4.8 Hz, 1H), 7.15 (dd, J = 11.2, 4.0 Hz, 1H), 7.04(dd, J = 9.0, 2.3 Hz, 1H), 6.81 (q, J = 4.8 Hz, 1H), 6.70 (d, J = 2.2Hz, 1H), 2.85 (d, J = 4.9 Hz, 3H). DMSO 371.1 (M + 1) Method B (NH₄HCO₃)95 Method AE

Method AG: 1-(Benzyloxy)-3-chloro-7-methoxyisoquinoline (xxxvii-a)

1,3-dichloro-7-methoxyisoquinoline (2.00 g, 8.8 mmol, 1.0 eq.) wasdissolved in 30 mL anhydrous toluene and sodium benzyloxide (2.30 g,17.6 mmol, 2.0 eq.) was added. The mixture was heated to 80° C. for 18h. TLC indicated the reaction was complete. The mixture was concentratedto give the crude product, which was purified by chromatography onsilica gel (eluted with petroleum ether) to give 2.20 g of xxxvii-a as awhite solid (84.6%). LCMS m/z=300.1, 302.0 (M+1) (Method B) (retentiontime=2.23 min).

1-(Benzyloxy)-7-methoxy-3-(pyridin-3-yl)isoquinoline (xxxviii-a)

1-(Benzyloxy)-7-methoxy-3-(pyridin-3-yl)isoquinoline was prepared usingMethod N2. 1-(Benzyloxy)-3-chloro-7-methoxyisoquinoline (93 mg, 0.5mmol, 1.0 eq.), potassium carbonate (357 mg, 2.5 mmol, 5.0 eq.), andPd(PPh₃)₂Cl₂ (18 mg, 0.026 mmol, 0.05 eq.) was dissolved in the mixedsolvent of 1,4-dioxane (3 mL) and water (1 mL). The resulting mixturewas stirred at 120° C. for 30 min under the microwave condition. Thesolid was filtrated off and the filtrate was concentrated. The residuewas partitioned between ethyl acetate and water. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate.After filtration and evaporation, the residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=1:10) to afford 100 mg ofxxxviii-a as a yellow solid (84.7%).

7-Methoxy-3-(pyridin-3-yl)isoquinolin-1-ol (xxxviv-a)

7-Methoxy-3-(pyridin-3-yl)isoquinolin-1-ol (prepared in a manneranalogous to that described for 2-amino-5-methoxybenzoic acid in MethodK, replacing 5-methoxy-2-nitrobenzoic acid with1-(benzyloxy)-7-methoxy-3-(pyridin-3-yl) isoquinoline) was obtained in a63.6% yield to give 280 mg of xxxviv-a as a yellow solid. This wascarried on without further purification,

1-Chloro-7-methoxy-3-(pyridin-3-yl)isoquinoline (xl-a)

1-Chloro-7-methoxy-3-(pyridin-3-yl)isoquinoline (prepared in a manneranalogous to that described for4-chloro-6-propoxy-2-pyridin-3-yl-quinazoline in Method F1, replacing6-propoxy-2-pyridin-3-yl-1H-quinazolin-4-one with3-(pyridin-3-yl)isoquinolin-1-ol) was obtained in a 73.0% yield to give60 mg of xl-a as a brown solid. MS m/z=241.1 (M+1) (Method A) (retentiontime=1.34 min).

N-(3-Chloro-4-fluorophenyl)-7-methoxy-3-(pyridin-3-yl)isoquinolin-1-amine(xli-a)

N—(N-(3-chloro-4-fluorophenyl)-7-methoxy-3-(pyridin-3-yl)isoquinolin-1-aminewas prepared using Method J. A mixture of1-chloro-7-methoxy-3-(pyridin-3-yl)isoquinoline (40 mg, 0.17 mmol, 1.0eq.), 3-chloro-4-fluoro aniline (30 mg, 0.21 mmol, 1.2 eq.), Pd₂(dba)₃(10 mg, 0.011 mmol, 0.06 eq.), Xantphos (15 mg, 0.026 mmol, 0.15 eq.),cesium carbonate (167 mg, 0.52 mmol, 3.0 eq.) was suspended in the mixedsolvent of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixturewas stirred at 120° C. for 30 min under the microwave conditions. Aftercooling, the resulting mixture was partitioned between water and ethylacetate. The combined organic layers were washed with water and brine,dried over anhydrous sodium sulfate. After filtration and evaporation,the residue was purified by prep-HPLC to afford 3 mg of xli-a as ayellow solid (yield 5.2%). LCMS m/z=380.1 (M+1) (Method B). ¹H NMR (400MHz, DMSO-d₆): δ 9.35 (s, 1H), 9.30 (d, J=2.0 Hz, 1H), 8.57 (dd, J=4.7,1.5 Hz, 1H), 8.41 (td, J=8.0, 1.8 Hz, 1H), 8.30 (dd, J=6.9, 2.6 Hz, 1H),7.94-7.87 (m, 4H), 7.43-7.49 (m, 3H), 3.99 (s, 3H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 43, replacing with the appropriateisoquinoline and aniline.

TABLE 15 Mo- Puri- Method lec- ¹H- ty for Num- Salt ular NMR LCMS per-Cou- ber PRODUCT type Mass ¹H-NMR Solvent LCMS Protocol cent pling 1100

379.81 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.35 (s, 1H), 9.30 (d, J = 2.0 Hz,1H), 8.57 (dd, J = 4.7, 1.5 Hz, 1H), 8.41 (td, J = 8.0, 1.8 Hz, 1H),8.30 (dd, J = 6.9, 2.6 Hz, 1H), 7.94-7.87 (m, 4H), 7.43-7.49 (m, 3H),3.99 (s, 3H). DMSO 380.1, 382.0 (M + 1) Method B (NH4HCO3) 95 Method J1101

411.38 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.46 (s, 1H), 9.31 (d, J = 1.75 Hz,1H), 8.57 (dd, J = 4.6, 1.3 Hz, 1H), 8.45-8.41 (m, 1H), 8.19 (s, 1H),7.99-7.94 (m, 2H), 7.91-7.86 (m, 2H), 7.54-7.44 (m, 3H), 7.01 (d, J =8.1 Hz, 1H), 4.00 (s, 3H). DMSO 412.1 (M + 1) Method B (NH4HCO3) 95Method J 1102

388.39 ¹H-NMR (400 MHz, DMSO-d₆): δ 11.35 (s, 1H), 9.34 (d, J = 1.9 Hz,1H), 8.80 (d, J = 8.4 Hz, 1H), 8.59 (dd, J = 4.7, 1.48 Hz, 1H),8.49-8.45 (m, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.97-7.92(m, 1H), 7.61 (td, J = 14.9, 7.5 Hz, 1H), 7.56-7.48 (m, 3H), 6.95 (dd, J= 10.3, 8.3 Hz, 1H), 3.98 (s, 3H). DMSO 389.1 (M + 1) Method B (NH4HCO3)95 Method J 1103

370.4 ¹H-NMR (400 MHz, CDCl3): δ 11.89 (s, 1H), 9.39 (s, 1H), 9.29 (s,1H), 8.63- 8.59 (m, 1H), 8.42- 8.37 (m, 1H), 7.75 (d, J = 8.8 Hz, 1H),7.60-7.62 (m, 4H), 7.44-7.33 (m, 3H), 7.05-7.00 (m, 1H), 4.06 (s, 3H).CDCl3 371.1 (M + 1) Method B (NH4HCO3) 95 Method J 1104

407.37 ¹H-NMR (400 MHz, CDCl3): δ 9.28 (s, 1H), 8.60 (d, J = 4.6 Hz,1H), 8.34 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.79 (d, J = 8.9 Hz, 1H),7.63 (s, 1H), 7.43- 7.35 (m, 2H), 7.22 (d, J = 8.6 Hz, 1H), 7.17 (s,1H), 7.09- 7.03 (m, 2H), 4.00 (s, 3H). CDCl3 408.1 (M + 1) Method B(NH4HCO3) 95 Method J 1105

454.4 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.00 (s, 1H), 9.43 (d, J = 1.2 Hz,1H), 9.35 (s, 1H), 8.63 (d, J = 3.7 Hz, 1H), 8.53 (s, 1H), 8.48-8.44 (m,1H), 8.03-8.09 (m, 3H), 7.97 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 1.8 Hz,1H), 7.56-7.50 (m, 2H), 7.05 (dd, J = 8.6, 1.93 Hz, 1H), 4.01 (s, 3H).DMSO 455.1 (M + 1) Method B (NH4HCO3) 95 Method J 1106

455.91 1H-NMR (400 MHz, DMSO-d₆): δ 9.65 (s, 1H), 9.37 (d, J = 1.7 Hz,1H), 8.83 (s, 1H), 8.63 (dd, J = 4.7, 1.3 Hz, 1H), 8.54-8.43 (m, 1H),8.35 (dd, J = 6.9, 2.6 Hz, 1H), 8.15 (dd, J = 8.5, 1.4 Hz, 1H), 8.03 (t,J = 4.3 Hz, 2H), 7.91- 7.95 (m, 1H), 7.46- 7.55 (m, 5H), 7.11-7.01 (m,1H), 3.91 (s, 3H). DMSO 456.1, 458.1 (M + 1) Method B (NH₄HCO₃) 95Method J 1107

¹H-NMR (400 MHz, DMSO-d₆): δ 9.63 (s, 1H), 9.36 (d, J = 1.9 Hz, 1H),9.19 (d, J = 1.9 Hz, 1H), 8.91 (s, 1H), 8.67 (dd, J = 4.8, 1.5 Hz, 1H),8.62 (dd, J = 4.7, 1.5 Hz, 1H), 8.53-8.44 (m, 1H), 8.35-8.32 (m, 2H),8.19 (dd, J = 8.5, 1.5 Hz, 1H), 8.13- 8.01 (m, 2H), 7.92 (ddd, J = 9.1,4.3, 2.7 Hz, 1H), 7.61 (dd, J = 7.9, 4.8 Hz, 1H), 7.55 (dd, J = 8.0, 4.8Hz, 1H), 7.50 (t, J = 9.1 Hz, 1H). DMSO 426.7 428.7 (M + 1) Method B(NH4HCO3) 95 Method J

Method AI: Ethyl 2-cyano-4,4-diethoxybutanoate (xlii-a)

2-Bromo-1,1-diethoxyethane (4 g, 20 mmol, 1.0 eq.) was added to amixture of ethyl 2 cyanoacetate (11.4 g, 101 mmol, 5.0 eq.), K₂CO₃ (2.8g, 20 mmol, 1.0 eq.) and NaI (200 mg, 1.3 mmol, 0.06 eq.), as describedin J. Chem. Soc., 1960, 131-138. The reaction mixture was refluxed for 4h at 145° C. After cooling, the reaction mixture was purified bychromatography on silica gel (eluted with petroleum ether/ethyl acetate(80:1→40:1→10:1) to give 3.57 g of xlii-a as a colorless oil (78%). ¹HNMR (400 MHz, CDCl₃): δ 4.70 (t, J=5.6 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H),3.78-3.64 (m, 3H), 3.62-3.45 (m, 2H), 2.35-2.14 (m, 2H), 1.34 (q, J=7.2Hz, 3H), 1.25-1.16 (m, 6H).

Method AJ: 2-(Pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (xliii)

To a solution of nicotinimidamide (5.03 g, 41.6 mmol, 1.2 eq.) in EtOH(100 mL), was added NaOMe (4.8 g, 88.8 mmol, 2.5 eq.). The mixture wasstirred at room temperature for 4 h. The reaction mixture was added toethyl 2-cyano-4,4-diethoxybutanoate (8.00 g, 34.9 mmol, 1 eq.). Thismixture was stirred at 105° C. overnight. After cooling, the reactionmixture was acidified with conc. HCl and stirred at room temperature for2 h. A precipitate formed and was collected and washed with H₂O (20mL×2). After lyophilization, 3.10 g of product: was obtained as a grayyellow solid (yield 41.8%). LCMS=213.1 (M+1) (Method B) (retentiontime=1.07 min)¹H NMR (400 MHz, DMSO-d₆): δ 12.26 (s, 1H), 12.04 (s, 1H),9.23 (d, J=1.6 Hz, 1H), 8.70 (dd, J=4.8, 1.2 Hz, 1H), 8.43-8.40 (m, 1H),7.55 (dd, J=8.0, 4.8 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 6.51 (d, J=2.8 Hz,1H).

4-Chloro-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (xlv-a)

4-Chloro-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (prepared in amanner analogous to that described for4-chloro-6-propoxy-2-pyridin-3-yl-quinazoline in Method F1 replacing6-propoxy-2-pyridin-3-yl-1H-quinazolin-4-one with2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol) to give 450 mg ofxliv-a in a 69.0% yield as a brown solid. LCMS m/z=231.0, 233.0 (M+1)(Method B) (retention time=1.60 min).

N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(xlv-a)

N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(prepared in a manner analogous to that described forN-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)propyl)-2-(pyridin-3-yl)quinazolin-4-amineusing Method G6, replacing3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propylmethanesulfonate with4-chloro-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine) to give a 11.3%yield, 10 Mg of xlv-a as brown solid. LCMS m/z=340.1, 342.0 (M+1)(Method B) (retention time=1.814 min). ¹H NMR (400 MHz, DMSO-d₆): δ 9.48(d, J=1.6 Hz, 1H), 8.62 (dd, J=4.8, 1.6 Hz, 1H), 8.60-8.56 (m, 1H), 8.27(dd, J=6.4, 2.4 Hz, 1H), 8.06 (ddd, J=8.8, 4.0, 2.8 Hz, 1H), 7.71 (d,J=3.6 Hz, 1H), 7.66 (t, J=9.2 Hz, 1H), 7.50 (dd, J=8.0, 4.8 Hz, 1H),7.41 (br s, 2H), 6.85 (d, J=3.6 Hz, 1H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 45, replacing with the appropriate aniline.

TABLE 16 Molec- ¹H- Method Num- Salt ular NMR LCMS Purity for berPRODUCT type Mass ¹H-NMR Solvent LCMS Protocol percent Coupling 1108

330.34 ¹H-NMR (400 MHz, DMSO-d₆): δ 12.29 (s, 1H), 12.09 (s, 1H), 9.54(d, J = 1.2 Hz, 1H), 9.11 (d, J = 8.4 Hz, 1H), 8.65-8.68 (m, 1H), 8.35(s, 1H), 7.89 (dd, J = 8.0, 1.2 Hz, 1H), 7.79 (s, 1H), 7.67 (td, J =8.8, 1.2 Hz, 1H), 7.55 (dd, J = 7.2, 4.8 Hz, 1H), 7.43-7.41 (m, 1H),7.10 (td, J = 8.0, 1.2 Hz, 1H), 6.49 (d, J = 3.6 Hz, 1H). DMSO 331.1(M + 1) Method B (NH4HCO3) 95 Method AJ, F, G6 1109

371.32 ¹H-NMR (400 MHz, DMSO-d₆): δ 12.02 (d, J = 1.3 Hz, 1H), 9.75 (s,1H), 9.50 (d, J = 1.5 Hz, 1H), 8.68-8.53 (m, 2H), 8.29 (s, 1H), 7.94-7.75 (m, 1H), 7.61- 7.44 (m, 2H), 7.41- 7.29 (m, 1H), 7.04 (s, 1H), 6.88(dd, J = 3.4, 1.9 Hz, 1H). DMSO 372.0 (M + 1) Method A (TFA) 95 MethodAJ, F, G6 1110

366.32 1H-NMR (400 MHz, DMSO-d6): δ 11.98 (s, 1H), 9.69 (s, 1H), 9.48(d, J = 1.8 Hz, 1H), 8.64-8.59 (m, 2H), 8.19 (d, J = 2.0 Hz, 1H), 7.63(dd, J = 8.8, 2.0 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 7.45 (d, J =8.8 Hz, 1H), 7.34 (d, J = 3.0 Hz, 1H), 6. DMSO 368.1 (M + 1) Method A(TFA) 95 Method AJ, F, G6 1111

339.75 ¹H-NMR (400 MHz, DMSO-d₆): δ 11.51 (s, 1H), 8.78 (d, J = 8.0 Hz,2H), 8.17 (d, J = 9.2 Hz, 1H), 7.80 (dd, J = 9.2, 2.8 Hz, 1H), 7.70-7.64(m, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.20 (d, J= 4.0 Hz, 2H), 7.16-7.08 (m, 1H). DMSO 340.1, 342.0 (M + 1) Method B(NH4HCO3) 95 Method AJ, F, G6

Method AK:4-Chloro-7-methyl-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (xliv-a)

To a solution of 4-chloro-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine(80 mg, 0.34 mmol, 1.0 eq.) in dry DMF (20 mL) was added Cs₂CO₃ (221 mg,0.68 mmol, 2.0 eq.) and iodomethane (54.3 mg, 0.38 mmol, 1.1 eq.) at 0°C. The reaction mixture was warmed to room temperature and stirred for2.5 h. The reaction mixture was poured into ice water and extracted withEtOAc (20 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄. After filtration and concentration, the residue was purified bychromatography on silica gel (petroleum ether/ethyl acetate 8:1) to give65 mg of xlvi-a as brown solid (56.7%).

N-(3-chloro-4-fluorophenyl)-7-methyl-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(xlvii-a)

N-(3-chloro-4-fluorophenyl)-7-methyl-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(prepared in a manner analogous to that described forN-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)propyl)-2-(pyridin-3-yl)quinazolin-4-amineusing Method G6, replacing3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propylmethanesulfonate with4-chloro-7-methyl-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine) to givea 70.0% yield, 30 mg of xlvii-a as a brown solid. LCMS m/z=354.1, 356.1(M+1) (Method B) (retention time=1.94 min). ¹H NMR (400 MHz, DMSO-d₆): δ9.97 (s, 1H), 9.53 (s, 1H), 9.15 (d, J=8.0 Hz, 1H), 8.91 (d, J=5.2 Hz,1H), 8.25 (dd, J=6.8, 2.4 Hz, 1H), 8.04 (dd, J=7.6, 5.6 Hz, 1H),7.94-7.90 (m, 1H), 7.48-7.43 (m, 2H), 6.95 (d, J=3.2 Hz, 1H), 3.88 (s,3H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 46, replacing with the appropriate aniline.

TABLE 17 Molec- ¹H- Method Num- Salt ular NMR LCMS Purity for berPRODUCT type Mass ¹H-NMR Solvent LCMS Protocol percent Coupling 1112

HCl 353.78 ¹H NMR (400 MHz, DMSO-d₆): δ 9.97 (s, 1H), 9.53 (s, 1H), 9.15(d, J = 8.0 Hz, 1H), 8.91 (d, J = 5.2 Hz, 1H), 8.25 (dd, J = 6.8, 2.4Hz, 1H), 8.04 (dd, J = 7.6, 5.6 Hz, 1H), 7.94-7.90 (m, 1H), 7.48-7.43(m, 2H), 6.95 (d, J = 3.2 Hz, 1H), 3.88 (s, 3H). DMSO 354.1, 356.1(M + 1) Method B (NH4HCO3) 95 Method AK, G6 1113

385.34 ¹H NMR (400 MHz, DMSO-d₆): δ 9.81 (s, 1H), 9.56 (d, J = 1.6 Hz,1H), 8.69- 8.64 (m, 2H), 8.29 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.55-7.51 (m, 2H), 7.41 (d, J = 3.6 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.90(d, J = 3.6 Hz, 1H), 3.87 (s, 3H). DMSO 386.1 (M + 1) Method B (NH4HCO3)95 Method AK, G6 1114

1H-NMR (400 MHz, DMSO-d6): δ 12.32 (s, 1H), 9.61 (s, 1H), 9.11 (d, J =7.6 Hz, 1H), 9.11 (d, J = 7.6 Hz, 1H), 8.74 (dt, J = 8.0, 1.9 Hz, 1H),8.67 (d, J = 3.6 Hz, 1H), 8.38 (s, 1H), 8.38 (s, 1H), 7.90 (dd, J = 7.9,1.4 Hz, 1H), 7.82 (s, 1H), 7.68 (dd DMSO 344.9 (M + 1) Method B(NH4HCO3) 95 Method AK, G6

Method AL:4-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)-2-(pyridin-3-yl)quinazoline-6-carboxamide(xlviii-a)

To a suspension of4-oxo-2-(pyridin-3-yl)-1,4-dihydroquinazoline-6-carboxamide (prepared asdescribed in scheme 4) (100 mg, 0.376 mmol, 1.0 eq.) in dry DMF (20 mL)was added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (216 mg, 0.488 mmol, 1.3 eq.) anddiaza(1,3)bicyclo[5.4.0]undecene (114.5 mg, 0.752 mmol, 2.0 eq.)following a procedure outlined in J. Org. Chem., 2007, 72, 1019440210.To the clear solution was then added 5,6-dimethyl-1H-benzo[d]imidazole(165.2 mg, 1.13 mmol, 3.0 eq.) and the mixture was stirred overnight atroom temperature. The resultant precipitate was then collected byfiltration and washed with dichloromethane, water, and ether. Theproduct was dried in vacuo to give 26.3 mg of the desired product:(xlviii-a) as an off-white solid (6.7%). LCMS m/z=395.1 (M+1) (Method C)(retention time=1.68 min). ¹H NMR (300 MHz, DMSO) δ 9.69 (s, 1H), 8.90(s, 1H), 8.82 (d, J=15.2 Hz, 2H), 8.66 (s, 1H), 8.54 (d, j=8.6 Hz, 1H),8.42 (s, 1H), 8.30 (d, J=8.5 Hz, 1H), 7.79 (s, 1H), 7.68 (s, 3H), 2.39(s, 3H), 2.36 (s, 3H).

Method AM: Synthesis of2-(6-(2-(piperidin-1-yl)ethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide(xlviv-a)

To 1-(2-chloroethyl)piperidine (45 μmol) was added the solution of2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (30 μmol) inNMP (200 μL) PS-BEMP (90 μmol) was added to the vials by resindispenser. After the reaction mixture was heated at 90° C. for 12 h, theresidue was diluted with methanol and purified by mass triggeredPREP-HPLC Condition D. The target fraction was lyophilized to afford thetitled compound whose structure was finally confirmed by LCMS using LCMSMethod E.

The compounds in the following table were prepared in a manner analogousto that described in Scheme 51, replacing 1-(2-chloroethyl)piperidinewith the appropriate alkyl halide.

TABLE 18 Mass Found Pur- Num- Starting Starting Salt Exact (M + ity berMaterial 1 Material 2 Product Type Mass 1) (%) 1116

468 469 98 1117

454 455 98 1118

456 457 98 1119

468 469 98 1120

482 483 98 1121

TFA 496 497 98 1122

465 466 98 1123

505 506 98

To a suspension of ethyl2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)-4-phenylthiazole-5-carboxylate(1.3956 g, 2.89 mmol) in dioxane (40 mL) was added 1N NaOH (20 ml, 20.00mmol) at room temperature to give a clear solution. The reaction mixturewas stirred at room temperature for 1 h and then warmed to 50° C.overnight, however starting material remained. An additional 20 mL of 1NNaOH was added and heating was continued at 50° C. for 1 h and at 70° C.for 5 h 30 min. The reaction mixture was cooled to room temperature anddiluted with water and ethyl acetate. The water phase was removed andadjusted to an acidic pH with 1N HCl (40 mL). A precipitate formed andwas collected and washed with water. The product was dried in vacuo togive 1.20 g of a brown solid in a 91% yield, ¹H NMR (DMSO-d₆) ppm 12.88(hr, 2H), 9.77 (dd, J=2.12, 0.6 Hz, 1H), 8.92-8.89 (m, 1H), 8.78 (dd,J=4.8, 1.68 Hz, 1H), 8.32 (br, 1H), 7.96 (d, J=9.12 Hz, 1H), 7.82-7.80(m, 2H), 7.70-7.67 (m, 1H), 7.63 (dd, J=9.12, 2.68 Hz, 1H), 7.50-7.44(m, 3H), 3.98 (s, 3H).

Method AN:2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)-N-methyl-4-phenylthiazole-5-carboxamide

To a suspension of2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)-4-phenylthiazole-5-carboxylicacid (291.8 mg, 0.641 mmol) in DMF (20 mL) under nitrogen atmosphere wasadded N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (189mg, 0.986 mmol) and 1-hydroxybenzotriazole hydrate (147 mg, 0.961 mmol)at room temperature. The reaction mixture was stirred at roomtemperature for 10 min to give a clear solution and methylamine in amethanol solution (4 mL) was added at room temperature. The reactionmixture was stirred at room temperature for 2 h 15 min. Additionalmethyl amine in a methanol solution (4 mL) was added at room temperatureand then heated to 50° C. for 1 h followed by room temperature for 2days. The reaction mixture was partitioned between water and ethylacetate. The water phase was collected and a solid precipitated from thewater phase. The solid was filtered and dried in an oven at 60° C. togive 107.9 mg (0.23 mmol) as the parent compound. The parent compoundwas suspended in methanol and 4N HCl in ethyl acetate (ca. 2 mL) wasadded to give a clear solution which precipitated over time. The solidwas collected by filtration and dried in oven at 60° C. for 2 days togive 82.4 mg of the HCl salt as a yellow solid in 24% yield. ¹H NMR(DMSO-d_(c)) δ 12.77 (brs, 1H), 9.76 (d, J=1.72. Hz, 1H), 9.18 (d,J=7.88 Hz, 1H), 8.92 (d J=5.04 Hz, 1H), 8.35 (brs, 1H), 8.27 (brd,J=4.56 Hz, 1H), 7.99-7.965 (m, 2H), 7.79 (brd, J=7.16 Hz, 2H), 7.65 (dd,J=9.12, 2.56 Hz, 1H), 7.50-7.41 (m, 3H), 4.00 (s, 3H), 2.76 (d, J=4.56Hz, 3H). The 1H of 2HCl was not observed.

The compounds in the following table were prepared in a manner analogousto that described in Scheme 53, replacing N-methyl amine with theappropriate alkyl amine.

TABLE 19 Starting Starting Salt Number Material 1 Material 2 ProductType 1124

2 HCl 1125 NH₃

2 HCl 1126

Method ¹H NMR Purity of Number ¹H NMR Solvent percent Coupling 1124 1HNMR (DMSO-d6) ppm 12.77 (brs, 1H), 9.76 (d, J = 1.72 Hz, 1H), 9.18 (d, J= 7.88 Hz, 1H), 8.92 (d J = 5.04 Hz, 1H), 8.35 (brs, 1H), 8.27 (brd, J =4.56 Hz, 1H), 7.99-7.965 (m, 2H), 7.79 (brd, J = 7.16 Hz, 2H), 7.65 (dd,J = 9.12, 2.56 Hz, 1H), 7.50-7.41 (m, 3H), 4.00 (s, 3H), 2.76 (d, J =4.56 Hz, 3H). The 1H of 2HCl was not observed. DMSO >98 Method AN 11251H NMR (DMSO-d6) ppm 12.75 (brs, 1H), 9.77 (d, J = 1.52 Hz, 1H), 9.13(brs, 1H), 8.88 (brd, J = 5.08 Hz, 1H), 8.34 (d, J = 2.04 Hz, 1H), 7.98(d, J = 9.12 HZ, 1H), 7.90 (brm, 1H), 7.83-7.80 (m, 2H), 7.66-7.53 (brm,3H), 7.51-7.42 (m, 3H), 4.00 (s, 3H). The 1H of 2HCl was not observed.DMSO >98 Method AN 1126 1H NMR (DMSO-d6) ppm 12.66 (s, 1H), 9.76 (s,1H), 8.88 (d, J = 7.76 HZ, 1H), 8.75 (d, J = 3.68 Hz, 1H), 8.40-8.20(br, 2H), 7.94 (br, 1H), 7.80 (d, J = 7.16 Hz, 2H), 7.63 (m, 2H),7.49-7.41 (m, 3H), 3.99 (s, 3H), 3.24 (q, J = 7.24 Hz, 2H), 1.07 (t, J =7.24 Hz, 3H) DMSO >98 Method AN

Method AO:N-tert-butyl-2-(4-(3,4-difluorophenyl-amino)-2-(pyridin-3-yl)quinazolin-6-yloxy)acetamide

To a solution of carboxylic acid derivative (500 mg, 1.2 mmol) in UMPwas added 2-aminoisobutane (134 mg, 1.8 mmol), NMM (0.4 mL, 3.6 mmol),WSCDI (282 mg, 1.4 mmol) and HOBT (22.5 mg, 1.4 mmol). The reactionmixture was stirred at room temperature overnight. The resultingsolution was poured into ice-water and the precipitate formed and wasfiltered off. The solid was washed with water and dried to give 350 mg(62% yield) of desired product, ¹H NMR (400 MHz, DMSO) δ 9.86 (s, 1H),9.49 (d, J=1.5 Hz, 1H), 8.71-8.57 (m, 2H), 8.11 (ddd, J=13.3, 7.5, 2.5Hz, 1H), 8.00-7.93 (m, 1H), 7.87 (d, J=9.1 Hz, 1H), 7.67 (ddd, J=11.7,7.1, 2.1 Hz, 2H), 7.59-7.47 (m, 3H), 4.61 (s, 2H), 1.35 (s, 9H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 54, replacing 2-aminoisobutane with theappropriate alkyl amine.

TABLE 20 Starting Starting Number Material R¹ Material R³ Product 1127

1128

1129

Method Salt ¹H NMR Purity of Number Type ¹H NMR Solvent percent Coupling1127 3 HCl ¹H NMR (400 MHz, DMSO) δ 10.60 (s, 1H), 9.48 (d, J = 1.9 Hz,1H), 9.14 (dt, J = 8.2, 1.6 Hz, 1H), 8.96 (dd, J = 5.5, 1.3 Hz, 1H),8.37 (t, J = 6.0 Hz, 1H), 8.24 (d, J = 2.6 Hz, 1H), 8.11-7.97 (m, 3H),7.74 (ddd, J = 11.8, 7.4, 3.3 Hz, 2H), 7.55 (dt, J = 10.5, 9.1 Hz, 1H),4.79 (s, 2H), 3.01 (t, J = 6.5 Hz, 2H), 1.86-1.59 (m, 1H), 0.85 (d, J =6.7 Hz, 6H). DMSO >98 Method AO 1128 3 HCl ¹H NMR (400 MHz, DMSO) δ10.81 (s, 1H), 9.50 (d, J = 1.9 Hz, 1H), 9.16 (d, J = 8.2 Hz, 1H), 8.98(dd, J = 5.5, 1.3 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 8.29 (t, J = 6.4Hz, 1H), 8.18-7.95 (m, 3H), 7.83-7.67 (m, 2H), 7.55 (dt, J = 10.5, 9.1Hz, 1H), 4.88 (s, 2H), 2.98 (d, J = 6.4 Hz, 1H), 0.84 (s, 9H). DMSO >98Method AO 1129 2 HCl ¹H NMR (400 MHz, DMSO) δ 10.87 (s, 1H), 9.50 (d, J= 1.9 Hz, 1H), 9.16 (d, J = 8.2 Hz, 1H), 8.98 (dd, J = 5.5, 1.3 Hz, 1H),8.41 (d, J = 2.5 Hz, 1H), 8.23-7.96 (m, 4H), 7.85-7.66 (m, 2H), 7.55(dt, J = 10.5, 9.1 Hz, 1H), 4.85 (s, 2H), 3.80-3.43 (m, 1H), 1.65-1.21(m, 4H), 0.81 (t, J = 7.4 Hz, 6H). DMSO >98 Method AO

2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)-1,N-dimethyl-1H-benzo[d]imidazole-1-carboxamide(334.1 mg, 0.760 mmol) was dissolved in concentrated HCl (0.063 ml,0.760 mmol). The solution was stirred at room temperature overnight andthen at 50° C. for 3 h 30 min followed by 100° C. for 3 h. The solid wascollected and dried in vacuo to give 116.2 mg of a yellow solid in ayield 35%. ¹H NMR (DMSO-d₆) δ 13.22 (br, 1H), 9.55 (s, 1H), 8.92 (dd,J=4.96, 1.36 Hz, 1H), 8.88 (br, 1H), 8.01 (d, J=9.12 Hz, 1H), 7.92 (br,1H), 7.83 (br, 1H), 7.67 (dd, J=9.12, 2.80 Hz, 1H), 7.61 (m, 2H), 7.38(m, 2H), 3.97 (s, 3H). The 1H of 2HCl and NH— were not observed.

4-(4-chlorophenyl)-2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)-N,N-dimethyl-1H-imidazole-1-carboxamideand concentrated HCl_((aq)) (10 mL) were added to a round bottom flask,a precipitate appeared upon refluxing the mixture for 3 h. The solid wascollected (373.4 mg) and tritiated with CH₂Cl₂/methanol overnight. Theproduct was filtered and dried to give 261.7 mg of a solid. A suspensionof the product in methanol was added to a 1N solution of NaOH_((aq.)) (5nit) followed by CH₂Cl₂ and H₂O. The solid was collected and washed withmethanol to give 255.7 mg (0.596 mmol) of the parent product. The freeparent was suspended in CH₂Cl₂/methanol and converted to the HCl salt byaddition of a 0.3 ml solution of 4N HCl in ethyl acetate. The HCl saltwas collected and dried in vacuo to give 248.4 mg as brown solid in a26% yield. ¹H NMR (DMSO-d₆) δ 13.61 (br, 1H), 12.81 (br, 1H), 9.46 (s,1H), 8.87 (d, J=5.24 Hz, 1H), 8.70 (br, 1H), 7.91-7.87 (m, 5H), 7.75 (m,1H), 7.62-7.56 (m, 3H), 3.95 (s, 3H). The 1H ref 2HCl was not observed.

To a mixture ofN-(6-(benzyloxy)-2-(pyridin-3-yl)quinazolin-4-yl)-4-(4-chlorophenyl)thiazol-2-amineand catechol, dimethyl ether (0.16 g, 1.15 mmol) was addedmethanesulfonic acid (4.0 mL). The mixture was stirred for 1 hr and wasthen poured into water. The slurry was added to a stirring sat.NaHCO_(3(aq)), solution slowly and allowed to stir for 30 min. Theprecipitate was filtered to give a brown solid which was washed withmethanol to give4-(4-(4-chlorophenyl)thiazol-2-ylamino)-2-(pyridin-3-yl)quinazolin-6-ol(0.23 g, 91.0%).

Scheme 59: Synthesis of4-(4-phenylthiazol-2-ylamino)-2-(pyridin-3-34)quinazolin-6-ol (Compound1133)

Synthesis of4-(4-phenylthiazol-2-ylamino)-2-(pyridin-3-yl)quinazolin-6-ol wasperformed in a similar manner to that described for4-(4-(4-chlorophenyl)thiazol-2-ylamino)-2-(pyridin-3-yl)quinazolin-6-olsubstituting for4-(4-phenylthiazol-2-ylamino)-2-(pyridin-3-yl)quinazolin-6-ol for theN-(6-(benzyloxy)-2-(pyridin-3-yl)quinazolin-4-yl)-4-(4-chlorophenyl)thiazol-2-aminegiving 4-(4-phenylthiazol-2-ylamino)-2-(pyridin-3-yl)quinazolin-6-ol. ¹HNMR (300 MHz, DMSO) δ 10.06-9.22 (m, 2H), 8.95 (dt, J=7.9, 1.6 Hz, 1H),8.62 (dd, J=4.7, 1.4 Hz, 1H), 7.99 (d, J=7.5 Hz, 2H), 7.87 (d, J=2.8 Hz,1H), 7.59-7.47 (m, 2H), 7.45-7.32 (m, 3H), 7.30-7.09 (m, 2H).

To a mixture of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (0.50 g,1.84 mmol) and 5′-fluorospiro[[1,3]-dioxolane-2,3′-indolin]-2′-one (0.42g, 2.02 mmol) in dry DMSO (4 mL) was added KOH powder (0.11 g, 2.02mmol). The reaction mixture was stirred for 15 h at room temperature andthen the reaction mixture was poured into water. The aqueous layer waswashed with ethyl acetate 20 mL) and the resulting aqueous layer wasacidified with 5N HCl to give a precipitate. The solid was filtered togive2-(5-fluoro-2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)phenyl)-1,3-dioxolane-2-carboxylicacid as a light yellow powder (0.27 g, 0.58 mmol, 32%). LCMS m/z=432(M+1) (Method C) ¹H NMR (300 MHz, DMSO) δ 9.50-9.38 (m, 2H), 8.69-8.59(m, 2H), 8.42 (dd, J=9.7, 5.3 Hz, 1H), 7.86 (d, J=9.1 Hz, 1H), 7.64 (d,J=2.6 Hz, 1H), 7.61-7.41 (m, 4H), 4.25-4.11 (m, 4H), 3.98 (s, 3H).

In a 50 mL round-bottomed flask was added 2,4-dichloro-6-iodoquinazoline(0.52 g, 1.6 mmol), 3-chloro-4-fluoroaniline (0.30 g, 2.1 mmol), andsodium acetate (0.20 g, 2.4 mmol) in THF (6 mL) and water (2 mL) to givea brown suspension. After being stirred at room temperature for 6 days,the reaction mixture was diluted with water (15 mL) and extracted withethyl acetate (2×10 mL). The organic layers were combined and washedwith brine (1×20 mL), dried over Na₂SO₄, filtered and concentrated. Theresulting product, was washed with CH₂Cl₂ and dried to give 0.51 g of2-chloro-N-(3-chloro-4-fluorophenyl)-6-iodoquinazolin-4-amine as a tightbrown solid in a 73% yield, ¹H NMR (300 MHz, DMSO) δ 10.29 (s, 1H), 8.95(s, 1H), 8.14 (dd, J=1.5, 9.0 Hz, 1H), 8.06 (dd, J=2.7, 6.6 Hz, 1H),7.81-7.76 (m, 1H), 7.52-7.46 (m, 2H).

In a 50 mL round-bottomed flask was added2-chloro-N-(3-chloro-4-fluorophenyl)-6-iodoquinazolin-4-amine (200 mg,0.46 mmol), N,N-dimethylpropargylamine (99 mL, 0.92 mmol), NEt₃ (0.26mL, 1.84 mmol), CuI (0.88 mg, 4.6 mmol) and PdCl₂(PPh₃)₂ (6.5 mg, 9.2mmol) in DMF (3 mL) to give a light yellow suspension. The mixture wasstirred at room temperature overnight under an argon atmosphere. Thereaction mixture was diluted with water (10 mL) and ethyl acetate (10mL) and then a precipitate formed. The resulting precipitate was removedby filtration through Celite. The filtrate was extracted with ethylacetate (2×10 mL). The combined organic layer was washed with water(1×15 mL) and brine (1×15 mL) and was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel (eluted with CH₂Cl₂/MeOH 1:0 to 9:1). The desired product waswashed with CH₂Cl₂ to give 61 mg of2-chloro-N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)quinazolin-4-amine,as pale yellow solid in a 34% yield. LCMS m/z=389 (M+1) (Method C)(retention time=2.2.4 min). ¹H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 8.68(s, 1H), 8.07 (dd, J=2.7, 6.9 Hz, 1H), 7.86 (dd, J=1.8, 8.7 Hz, 1H),7.81-7.70 (m, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.49 (t, J=9.2 Hz, 1H), 3.52(s, 2H), 2.28 (s, 6H).

In a 50 mL round-bottomed flask was added2-chloro-N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)quinazolin-4-amine,(61 mg, 0.16 mmol), 3-pyridineboronic acid (25 mg, 0.20 mmol), K₂CO₃(0.11 mg, 0.78 mmol) and PdCl₂(PPh₃)₂, (5.5 mg, 7.8 mM) in dioxane (2mL) to give a yellow suspension. The mixture was heated at reflux for 3h under argon. After cooling to room temperature, water (10 mL) andethyl acetate (10 mL) were added to the mixture to form a precipitate.The resulting precipitate was filtered through Celite. The filtrate wasextracted with ethyl acetate (2×10 mL) and the combined organic layerswere washed with water (1×15 mL) and brine (1×15 mL) and then dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography on silica gel (eluted with AcOEt/MeOH 1:0 to 9:1). Thedesired product was washed with CH₂Cl₂ to give 25 mg ofN-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)-2-(pyridin-3-yl)quinazolin-4-amineas a light brown solid in 37% yield. LCMS m/z=432 (M+1) (Method C)(retention time=1.86 ruin). ¹H NMR (300 MHz, DMSO) δ 10.13 (s, 1H), 9.51(s, 1H), 8.77-8.56 (m, 3H), 8.26 (dd, J=6.9, 2.5 Hz, 1H), 8.02-7.78 (m,3H), 7.64-7.47 (m, 2H), 3.54 (s, 2H), 2.30 (s, 6H).

A mixture of 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide(200 mg, 0.283 mmol), (isocyanatomethyl)benzene (5 mL) and Et₃N (57 mg,0.283 mmol) in tetrahydrofuran (THF) (10 in T) was stirred at roomtemperature overnight. Water (10 mL) was added to the above mixture andthe mixture was concentrated in vacuo. The precipitate was collected byfiltration and washed with water (6 mL×2) to afford 72 mg of the desiredproduct as a white solid in a yield 26.0%. LCMS: rt=1.829 min,[MH]⁺=491.1 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.05 (s, 1H), 9.63 (s, 1H),9.07 (d, J=8.5 Hz, 1H), 8.87 (d, J=8.0 Hz, 1H), 8.79 (d, J=3.7 Hz, 1H),8.59 (t, J=6.1 Hz, 1H), 8.49 (s, 1H), 8.02-7.89 (m, 4H), 7.82-7.68 (m,3H), 7.46-7.22 (m, 6H), 4.35 (d, J=6.1 Hz, 2H).

4-(2-carbamoylphenylamino)-2-(pyridin-3-yl)quinazolin-6-ylethylcarbamate was synthesized in a similar manner to that described for4-(2-carbamoylphenylamino)-2-(pyridin-3-yl)quinazolin-6-ylbenzylcarbamate substituting isocyanatoethane for(isocyanatomethyl)benzene. The resulting product was analyzed by LCMS:rt=1.11 min, [M+1]⁺=429.0, ¹H-NMR (400 MHz, DMSO-d₆): δ 13.06 (s, 1H),9.66 (s, 1H), 9.10 (d, J=8.3 Hz, 1H), 8.87-8.80 (m, 2H), 8.51 (s, 1H),8.06-7.94 (m, 4H), 7.88 (s, 1H), 7.79-7.63 (m, 3H), 7.24 (t, J=7.6 Hz,1H), 3.22-3.11 (m, 2H), 1.14 (t, J=7.2 Hz, 3H).

A mixture of4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazoline-carbonitrile(1.5 g, 4.0 mmol) in HCl (conc, 25 mL) was heated to 100° C. and stirredovernight. After cooling and filtration, the solid was washed with water(10 mL) twice to give 1.4 g of the desired product4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazoline-6-carboxylicacid as a yellow solid in a 89.0% yield. LCMS: r.t=1.271 min,[M+H]⁺=394.9

A mixture of4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazoline-6-carboxylicacid (900 mg, 2.4 mmol), DIPEA (620 mg, 4.8 mmol) and HATU (1.4 g, 3.6mmol) in DMF (10 mL) was pre-stirred for 20 min, and2,2,2-trifluoro-N-methylethanamine (360 mg, 2.4 mmol) was added in oneportion. The resulting mixture was stirred at room temperatureovernight. Water (80 mL) was added and a precipitate formed which wascollected and purified by prep-HPLC to afford 490 mg of the desiredproduct4-(3-chloro-4-fluorophenylamino)-N-methyl-2-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)quinazoline-6-carboxamideas a white solid in 42.0% yield. LCMS: r.t=1.970 min, 490.0 ¹H-NMR (400MHz, DMSO-d₆): δ 10.79 (brs, 1H), 9.59 (s, 1H), 9.19 (d, J=7.6 Hz, 1H),9.04 (d, J=4.8 Hz, 1H), 8.90 (s, 1H), 8.22-8.00 (m, 5H), 7.62 (t, J=9.2Hz, 1H), 4.55-4.52 (m, 2H), 3.22 (s, 3H).

To a mixture of4-(3-chloro-4-fluorophenylamino)-N-methyl-2-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)quinazoline-6-carboxamide(60 mg, 0.12 mmol) THF (1 mL) was added BH₃-THF (2 mol/L, 1 mL). Themixture was stirred at room temperature overnight. Methanol (0.2 mL) wasadded to quench the reaction mixture. The mixture was purified byprep-HPLC to give the desired productN-(3-chloro-4-fluorophenyl)-6-((methyl(2,2,2-trifluoroethyl)amino)methyl)-2-(pyridin-3-yl)quinazolin-4-amine(GL0001H-3309) as a white solid 15 mg in a yield of 26.0%. LCMS:r.t=2.154 min, [MH]⁺=476.1. ¹H-NMR (400 MHz, DMSO-d₆): δ 10.09 (s, 1H),9.53 (s, 1H), 8.70-8.66 (m, 2H), 8.44 (s, 1H), 8.27-8.25 (m, 1H),7.93-7.91 (m, 3H), 7.57-7.55 (m, 2H), 3.93 (s, 2H), 3.39-3.32 (m, 2H),2.40 (s, 3H).

Synthesis of4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)quinazoline-6-carboxamide(compound 1139)

4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)quinazoline-6-carboxamidewas synthesized in a similar manner to that described for4-(3-chloro-4-fluorophenylamino)-N-methyl-2-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)quinazoline-6-carboxamidesubstituting 2,2,2-trifluoroethylamine for2,2,2-trifluoro-N-methylethylamine. The resulting product was analyzed.LCMS: r.t=1.934 min, [M+1]⁺=476.0. ¹H-NMR (400 MHz, DMSO-d₆): δ 10.43(s, 1H), 9.54 (s, 1H), 9.32 (t, J=6.1 Hz, 1H), 9.14 (s, 1H), 8.72 (d,J=4.6 Hz, 1H), 8.68 (d, J=8.0 Hz, 1H), 8.32 (d, J=8.7 Hz, 1H), 8.27 (dd,J=6.7, 2.2 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.96-7.90 (m, 1H), 7.62-7.51(m, 2H), 4.27-4.14 (m, 2H).

Method E for CyclizationE1: Sodium methoxide/TolueneE2: NaOH/EtOHMethod G for Coupling ConditionsG1: i-PrOH/85-100° C.G2: THF/refluxG3: i-AmOH/100-130° C.G4: MeOH/microwave/150° C.G5: i-AmOH/microwave/150° C.G6: THF/Et₃N/reflux

Method D: N-(2-carbamoylphenyl)pyridazine-4-carboxamide (iii-c)

A mixture of pyridazine-4-carboxylic acid (500 mg, 4.0 mmol, 1.0 eq.),2-aminobenzamide (603 mg, 4.4 mmol, 1.1 eq.) and HBTU (3.0 g, 8.0 mmol,2.0 eq.) was suspended in 15 mL of DMF. DIPEA (2.0 mL, 1.56 g, 12.0mmol, 3.0 eq.) was added dropwise at room temperature and was stirredover night. After quenching with water, the resulting precipitate wascollected and washed with a small amount of DCM. A white solid (388 mg)was obtained, LCMS m/z=243.1 (M+1) (Method B) (retention time=0.99 min)was used in the next step without further purification.

Method E1: 2-(pyridazin-4-yl)quinazolin-4(3H)-one (iv-f)

A 100 mL round-bottom flask equipped with a Dean-Stark trap was chargedwith a mixture of N-(2-carbamoylphenyl)pyridazine-4-carboxamide (300 mg,1.0 eq.), sodium methoxide (401 mg, 7.4 mmol, 6.0 eq.) and 10 mL ofanhydrous toluene. The reaction mixture was heated to 110° C. andrefluxed overnight. After cooling, the volatiles were removed in vacuoand the residue was quenched with a saturated aqueous solution of NH₄Cl(10 mL). The pH of the mixture was adjusted to 3 with 10% HCl in water.The solution was extracted with DCM (50 ml×3). The combined organiclayers were washed with brine, dried over Na₂SO₄. After filtration andevaporation, 88 mg of a yellow solid was obtained, LCMS m/z=225.1 (M+1)(Method A) (retention time=1.10 min) which was used in the next stepwithout further purification.

Method F5: 4-chloro-2-(pyridazin-4-yl)quinazoline (v-f)

A 100-mL round-bottom flask was charged with 2-(pyridazin-4-yl)quinazolin-4(3H)-one (30 mg) which was suspended in 3 mL of POCl₃. Thereaction mixture was heated to reflux for 1 h. The reaction mixtureturned to a clear brown solution. After cooling, 50 mL of ice/water wascarefully added. An aqueous ammonia solution (25% by weight in water)was added dropwise to the mixture with stirring until the pH of themixture was adjusted to 7˜8. An internal temperature of 0° C. wasmaintained by the addition of ice. The mixture was warmed to roomtemperature and extracted with DCM (50 ml×3). The combined organiclayers were washed with brine, dried over Na₂SO₄. After filtration andevaporation, 32 mg was obtained as a light brown solid. LCMS m/z=242.9(M+1) (Method B) (retention time=1.65 min). The solid was used directlyin the next step without further purification.

Method G1: N-(3,4-difluorophenyl)-2-(pyridazin-4-yl)quinazolin-4-amine(vi-r)

(This method is representative of method G1, G2, and G3. These threemethods can be implemented in a similar way except for substitution ofthe appropriate solvent and temperature) The mixture of4-chloro-2-(pyridazin-4-yl)quinazoline (10 mg, 0.041 mmol, 1 eq.) and3,4-difluorobenzenamine (11 mg, 0.082 mmol, 2 eq.) was suspended ini-PrOH. The mixture was heated at 85° C. overnight. After cooling, theresulting precipitate was filtered and purified on HPLC (Condition C).7.3 mg of N-(3,4-difluorophenyl)-2-(pyridazin-4-yl)quinazolin-4-aminewas obtained (yield 53%). LCMS m/z=336.0 (M+1) (Method B) (retentiontime=1.731 min). ¹H-NMR (400 MHz, DMSO-d₆): δ 10.23 (s, 1H), 10.00 (dd,J=2.2, 1.3 Hz, 1H), 9.44 (dd, J=5.4, 1.2 Hz, 1H), 8.59 (d, J=8.1 Hz,1H), 8.39 (dd, J=5.4, 2.4 Hz, 1H), 8.05-8.13 (m, 1H), 7.99 (s, 1H), 7.97(d, J=3.6 Hz, 1H), 7.72-7.79 (m, 2H), 7.51-7.61 (m, 1H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 1 and 64 (prepared according to methodprocedure A-G as designated).

TABLE 21 Puri- Method Molec- ¹H- ty for Num- Salt ular NMR LCMS per-Coup- ber PRODUCT type Mass ¹H-NMR Solvent LCMS Protocol cent ling 1140

402.66 1H-NMR (400 MHz, CD3OD): δ 9.40 (s, 1H), 9.84-9.86 (m, 2H), 8.52(d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.84 (dd, J = 9.2, 2.4Hz, 1H), 7.66- 7.67 (m, 2H). CD3OD 402.0, 404.0, 405.9 (M + 1) Method B(NH4HCO3) 95 Method C, G1 1141

386.21 1H-NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 9.49 (s, 1H), 8.89(d, J = 10.8 Hz, 2H), 8.75 (d, J = 8.8 Hz, 1H), 8.44 (dd, J = 6.8, 2.4Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.94- 7.99 (m, 1H), 7.87 (dd, J =8.8, 2.0 Hz, 1H), 7.56 (t, J = 9.2 Hz, 1H). DMSO 386.0, 388.0 (M + 1)Method B (NH4HCO3) 95 Method C, G1 1142

369.76 1H-NMR (400 MHz, CD3OD): δ 9.40 (s, 1H), 8.76 (d, J = 10.8 Hz,2H), 8.40 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.80-7.86 (m,1H), 7.68 (dd, J = 8.8, 1.6 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.33 (q,J = 9.2 Hz, 1H). CD3OD 370.0, 372.1 (M + 1) Method B (NH4HCO3) 95 MethodC, G1 1143

376.8 1H-NMR (400 MHz, CD3OD): δ 9.55 (s, 1H), 8.80 (d, J = 7.2 Hz, 3H),8.26 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.72(d, J = 8.4 Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H).CD3OD 377.1, 379.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1 1144

358.78 1H-NMR (400 MHz, CD3OD): δ 9.39 (d, J = 1.6 Hz, 1H), 8.79 (d, J =6.8 Hz, 2H), 8.47 (d, J = 9.2 Hz, 1H), 8.20 (s, 1H), 8.05-8.10 (m, 2H),7.77 (dd, J = 8.8, 2.0 Hz, 1H), 7.63- 7.66 (m, 2H). CD3OD 359.0, 361.0(M + 1) Method B (NH4HCO3) 95 Method C, G1 1145

399.78 1H-NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H), 9.52 (d, J = 1.2 Hz,1H), 8.86 (t, J = 6.0 Hz, 2H), 8.77 (d, J = 8.4 Hz, 1H), 8.12 (d, J =15.6 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.53 (t, J = 8.0 Hz, 1H), 7.32(t, J = 74.0 Hz, 1H), 7.04 (dd, J = 8.0, 1.6 Hz, 1H). DMSO 400.0, 402.0(M + 1) Method B (NH4HCO3) 95 Method C, G1 1146

402.66 1H-NMR (400 MHz, CD3OD): δ 9.40 (s, 1H), 8.85-8.88 (m, 2H), 8.53(d, J = 9.2 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.80-7.88 (m, 3H), 7.46(s, 1H). CD3OD 401.9, 403.9, 405.9 (M + 1) Method B (NH4HCO3) 95 MethodC, G1 1147

377.78 1H-NMR (400 MHz, DMSO-d6): δ 12.28 (s, 1H), 9.58 (s, 1H), 9.14(d, J = 8.4 Hz, 1H), 8.87 (s, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.28 (d, J= 9.2 Hz, 1H), 8.07- 8.12 (m, 2H), 7.86 (dd, J = 8.8, 2.0 Hz, 1H), 7.77(t, J = 8.8 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H). DMSO 378.1, 380.0 (M + 1)Method B (NH4HCO3) 95 Method C, G1 1148

381.79 1H-NMR (400 MHz, DMSO-d6): δ 11.69- 11.49 (m, 1H), 9.40 (d, J =1.2 Hz, 1H), 9.00-8.86 (m, 3H), 8.24 (dd, J = 6.6, 2.1 Hz, 1H), 7.91(ddd, J = 8.9, 4.2, 2.6 Hz, 1H), 7.71 (d, J = 1.4 Hz, 1H), 7.61 (t, J =9.0 Hz, 1H), 7.49 (dd, J = 9.2, 2.3 Hz, 1H), 4.00 (s, 3H). DMSO 382.1,384.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1 1149

395.36 1H-NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1H), 9.57 (d, J = 1.4 Hz,1H), 8.83- 8.74 (m, 2H), 8.57 (d, J = 9.1 Hz, 1H), 8.28 (t, J = 2.0 Hz,1H), 7.86 (dd, J = 8.2, 1.2 Hz, 1H), 7.50-7.32 (m, 3H), 7.31 (t, J =74.0 Hz, 1H), 6.94 (dd, J = 8.0, 2.2 Hz, 1H), 3.98 (s, 3H). DMSO 396.1,(M + 1), 397.2 (M + 2) Method B (NH4HCO3) 95 Method C, G1 1150

383.33 1H-NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 9.57 (s, 1H), 8.80(dd, J = 19.8, 1.7 Hz, 2H), 8.72- 8.66 (m, 1H), 8.50 (s, 1H), 8.07-7.94(m, 3H), 7.75 (t, J = 7.2 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H), 7.14 (d, J= 8.8 Hz, 1H). DMSO 384.1 (M + 1) Method B (NH4HCO3) 95 Method C, G11151

385.42 1H-NMR (400 MHz, DMSO-d6): δ 13.01 (s, 1H), 10.04 (s, 1H), 9.40(d, J = 5.4 Hz, 1H), 9.20 (d, J = 8.4 Hz, 1H), 8.48 (s, 1H), 8.42 (dd, J= 5.3, 1.9 Hz, 1H), 8.04-7.94 (m, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.75(t, J = 7.9 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H),7.13 (s, 1H), 3.15 (s, 6H). DMSO 386.0 (M + 1) Method A (TFA) 95 MethodD, G1 1152

HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 9.97 (d, J = 1.1 Hz,1H), 9.55 (d, J = 5.5 Hz, 1H), 8.61 (dd, J = 5.5, 2.2 Hz, 1H), 8.15 (dd,J = 6.8, 2.6 Hz, 1H), 8.08 (d, J = 9.3 Hz, 1H), 7.94 (ddd, J = 8.9, 4.3,2.6 Hz, 1H), 7.74 (s, 1H), 7.62 (dd, J = 9.4, 2.5 Hz, 1H), 7.56 (t, J =9.1 Hz, 1H), 3.16 (s, 6H). DMSO 395.1, 397.1 (M + 1) Method A (TFA) 95Method D, G1 1153

HCl 408.4 1H-NMR (400 MHz, DMSO-d6): δ 10.71 (brs, 1H), 10.01-9.99 (m,1H), 9.52 (dd, J = 5.5, 1.0 Hz, 1H), 8.60 (dd, J = 5.5, 2.3 Hz, 1H),8.07 ((d, J = 9.2 Hz 1H), 7.85-7.78 (m, 2H), 7.71 (s, 1H), 7.65 (dd, J =9.3, 2.5 Hz, 1H), 7.56 (t, J = 8.2 Hz, 1H), 7.33 (t, J = 74.0 Hz, 1H),7.09 (dd, J = 8.1, 2.1 Hz, 1H), 3.17 (s, 6H). DMSO 409.1 (M + 1) MethodA (TFA) 95 Method D, G1 1154

372.38 1H-NMR (400 MHz, DMSO-d6): δ 13.13 (s, 1H), 9.63 (d, J = 1.2 Hz,1H), 9.34 (d, J = 7.6 Hz, 1H), 8.91- 8.84 (m, 1H), 8.79 (d, J = 2.4 Hz,1H), 8.49 (s, 1H), 8.12 (d, J = 9.6 Hz, 1H), 8.03- 7.85 (m, 2H), 7.75-7.61 (m, 1H), 7.48- 7.30 (m, 2H), 7.28- 7.06 (m, 1H), 3.99 (s, 3H). DMSO373.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1 1155

381.79 1H-NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 9.99-9.95 (m, 1H),9.42 (dd, J = 5.2, 1.2 Hz, 1H), 8.58-8.51 (m, 1H), 8.35 (dd, J = 5.2,2.4 Hz, 1H), 8.21 (dd, J = 6.8, 2.4 Hz, 1H), 7.93 (ddd, J = 8.8, 4.2,2.7 Hz, 1H), 7.53 (dd, J = 11.7, 6.4 Hz, 1H), 7.32 (dd, J = 6.6, 2.6 Hz,2H), 3.97 (s, 3H). DMSO 382.0, 384.0 (M + 1) Method B (NH4HCO3) 95Method D, G1 1156

395.36 1H-NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 10.01 (d, J = 1.3 Hz,1H), 9.43 (dd, J = 5.2, 1.2 Hz, 1H), 8.55 (d, J = 10.0 Hz, 1H), 8.40(dd, J = 5.2, 2.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.86- 7.77 (m, 1H),7.55-7.35 (m, 3H), 7.32 (t, J = 74.0 Hz, 1H), 7.01 (dd, J = 8.0, 2.0 Hz,1H), 3.99 (s, 3H). DMSO 396.1 (M + 1) Method B (NH4HCO3) 95 Method D, G11157

376.80 1H-NMR (400 MHz, DMSO-d6): δ 13.34 (s, 1H), 9.61 (d, 1H), 9.28(d, J = 8.4 Hz, 1H), 8.87 (s, 1H), 8.80 (s, 1H), 8.53 (s, 1H), 8.25 (s,1H), 7.94-8.06 (m, 4H), 7.70 (t, J = 8.0 Hz, 1H), 7.23 (t, J = 7.6 Hz,1H). DMSO 377.0, 379.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1 1158

358.78 1H-NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 9.54 (s, 1H),8.77-8.84 (m, 4H), 8.32 (d, J = 8.0 Hz, 1H), 8.00-8.03 (m, 2H),7.62-7.70 (m, 2H). DMSO 359.0, 361.0 (M + 1) Method B (NH4HCO3) 95Method C, G1 1159

386.21 1H-NMR (400 MHz, DMSO-d6): δ 10.55 (s, 1H), 9.50 (s, 1H), 8.838.87 (m, 3H), 8.47-8.49 (m, 1H), 7.96-8.06 (m, 3H), 7.54 (t, J = 9.2 Hz,1H). DMSO 386.0, 388.0, 390.0 (M + 1) Method B (NH4HCO3) 95 Method C, G11160

402.66 1H-NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 9.53 (s, 1H),8.84-8.88 (m, 3H), 8.62 (d, J = 2.0 Hz, 1H), 8.01-8.07 (m, 3H), 7.73 (d,J = 8.8 Hz, 1H). DMSO 401.9, 403.9, 406.0 (M + 1) Method B (NH4HCO3) 95Method C, G1 1161

402.66 1H-NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.55 (d, J = 1.6 Hz,1H), 8.87- 8.88 (m, 1H), 8.82 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 2.0 Hz,2H), 8.00-8.07 (m, 2H), 7.40 (t, J = 1.6 Hz, 1H). DMSO 401.9, 403.8,405.8 (M + 1) Method B (NH4HCO3) 95 Method C, G1 1162

468.25 1H-NMR (400 MHz, DMSO-d6): δ 13.36 (s, 1H), 9.59 (d, J = 1.2 Hz,1H), 9.15- 9.12 (m, 1H), 8.90- 8.85 (m, 2H), 8.68 (d, J = 1.2 Hz, 1H),8.52 (s, 1H), 8.28- 8.25 (m, 1H), 8.07 (s, 1H), 7.99-7.96 (m, 1H), 7.83(d, J = 8.8 Hz, 1H), 7.74-7.70 (m, 1H), 7.28 (t, J = 7.6 Hz, 1H). DMSO469.0 (M + 1) Method B (NH4HCO3) 90 Method C, G1 1163

491.23 1H-NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H), 9.32 (s, 1H), 9.07(s, 1H), 8.74 (s, 2H), 8.16 (dd, J = 8.0, 1.6 Hz, 1H), 7.87 (s, 1H),7.74- 7.64 (m, 2H), 7.39 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 74.0 Hz, 1H),6.96-6.92 (m, 1H). DMSO 492.0 (M + 1) Method B (NH4HCO3) 90 Method C, G11164

477.66 1H-NMR (400 MHz, DMSO-d6): δ 11.48 (s, 1H), 9.42 (s, 1H), 9.34(s, 1H), 8.95- 8.93 (m, 2H), 8.35- 8.30 (m, 2H), 7.97- 7.90 (m, 2H),7.60 (t, J = 9.0 Hz, 1H). DMSO 478.0, 480.0 (M + 1) Method B (NH4HCO3)90 Method C, G1 1165

413.81 1H-NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 9.99 (s, 1H), 9.40(d, J = 5.6 Hz, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.36 (dd, J = 5.2, 2.0Hz, 1H), 7.87 (m, 1H), 7.81 (m, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.30 (t,J = 74.0 Hz, 1H), 8.36 (dd, J = 8.4, 2.0 Hz, 1H), 2.70 (s, 3H). DMSO414.1, 416.0 (M + 1) Method B (NH4HCO3) 95 Method D, G1 1166

400.24 1H-NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 10.01 (s, 1H), 9.46(d, J = 5.2 Hz, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.39 (dd, J = 5.4, 2.2Hz, 1H), 8.20 (dd, J = 7.2, 2.6 Hz, 1H), 7.95-7.91 (m, 1H), 7.89 (s,1H), 7.57 (t, J = 9.0 Hz, 1H), 2.75 (s, 3H). DMSO 400.0, 402.0 (M + 1)Method B (NH4HCO3) 95 Method D, G1 1167

409.39 1H-NMR (400 MHz, DMSO-d6): δ 10.05- 10.3 (m, 2H), 9.45 (dd, J =5.2, 1.2 Hz, 1H), 8.42 (dd, J = 5.2, 1.2 Hz, 1H), 8.06 (d, J = 2.8 Hz,1H), 7.97-7.94 (m, 2H), 7.86 (dd, J= 8.0, 1.2 Hz, 1H), 7.66-7.60 (m,2H), 7.38 (t, J = 74.0 Hz, 1H), 7.10-7.08 (m, 1H), 4.32 (q, J = 6.8 Hz,2H), 1.51 (t, J = 7.0 Hz, 3H). DMSO 410.1 (M + 1) Method B (NH4HCO3) 95Method D, G1 1168

379.36 1H-NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 10.07 (d, J = 2.0 Hz,1H), 9.44 (dd, J = 5.2, 2.4 Hz, 1H), 8.48-8.44 (m, 2H), 7.93 (t, J = 2.0Hz, 1H), 7.86- 7.84 (m, 2H), 7.66- 7.62 (m, 1H), 7.54 (t, J = 8.4 Hz,1H), 7.32 (t, J = 74.0 Hz, 1H), 7.02 (dd, J = 8.0, 2.4 Hz, 1H), 2.77 (s,3H). DMSO 380.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1 1169

444.23 1H-NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 9.55 (s, 1H), 8.98(s, 1H), 8.79 (d, J = 12.8 Hz, 2H), 8.26 (s, 1H), 8.08 (d, J = 9.2 Hz,1H), 7.92-7.88 (m, 2H), 7.52-7.50 (m, 1H), 7.32 (t, J = 71.6 Hz, 1H),6.99 (d, J = 7.6 Hz, 1H). DMSO 444.0, 446.0 (M + 1) Method B (NH4HCO3)95 Method C, G1 1170

430.66 1H-NMR (400 MHz, DMSO-d6): δ 10.11 (s, 1H), 9.52 (s, 1H), 8.89(d, J = 1.2 Hz, 1H), 8.83 (s, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.56 (dd, J= 6.8, 2.4 Hz, 1H), 8.05 (dd, J = 9.2, 2.0 Hz, 1H), 8.02- 7.96 (m, 1H),7.88 (d, J = 8.8 Hz, 1H), 7.49 (t, J = 9.2 Hz, 1H). DMSO 430.0, 432.0,434.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1 1171

386.41 1H-NMR (400 MHz, DMSO-d6): δ 13.07 (s, 1H), 9.63 (s, 2H), 9.33(s, 1H), 8.95 (d, J = 8.0 Hz, 1H), 8.50 (s, 1H), 7.99- 7.94 (m, 3H),7.76- 7.71 (m, 1H), 7.62- 7.59 (m, 2H), 7.24 (t, J = 7.4 Hz, 1H), 4.23(q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H). DMSO 387.1 (M + 1) MethodB (NH4HCO3) 95 Method C, G1 1172

372.38 1H-NMR (400 MHz, DMSO-d6): δ 13.11 (s, 1H), 9.61 (s, 2H), 9.34(s, 1H), 8.91 (d, J = 8.0 Hz, 1H), 8.49 (s, 1H), 7.98- 7.95 (m, 3H),7.72 (t, J = 8.0 Hz, 1H), 7.62-7.60 (m, 2H), 7.24 (t, J = 7.6 Hz, 1H),3.97 (s, 3H). DMSO 373.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1 1173

HCl 379.32 1H-NMR (400 MHz, DMSO-d6): δ 10.55 (brs, 1H), 9.59 (s, 2H),9.35 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.09-8.07 (m, 1H), 8.00-7.96 (m,2H), 7.76-7.72 (m, 1H), 7.67 (dd, J = 8.8, 2.0 Hz, 1H), 7.53 (d, J = 8.8Hz, 1H). DMSO 380.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1 1174

HCl 464.47 1H-NMR (400 MHz, DMSO-d6): δ 10.14 (s, 1H), 9.59 (s, 1H),8.80 (m, 2H), 8.62 (d, J = 7.6 Hz, 1H), 8.30 (s, 1H), 7.90 (s, 2H), 7.70(d, J = 7.6 Hz, 1H), 7.53- 7.45 (m, 1H), 7.39- 6.86 (m, 1H), 7.30 (t, J= 74.1 Hz, 1H), 3.73 (s, 2H), 3.63- 3.58 (m, 4H), 2.48- 2.43 (m, 4H).DMSO 465.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1 1175

357.37 1H-NMR (400 MHz, DMSO-d6): δ 9.70 (s, 1H), 9.43 (d, J = 8.4 Hz,1H), 8.90 (s, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H),8.11 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.60-7.65 (m, 2H),7.09-7.13 (m, 3H), 2.76 (s, 3H). DMSO 358.0 (M + 1) Method B (NH4HCO3)95 Method C, G1 1176

365.79 1H-NMR (400 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.62 (s, 1H), 8.85(s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.03-8.07(m, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.49 (t, J= 9.2 Hz, 1H), 2.75 (s, 3H). DMSO 366.0, 368.0 (M + 1) Method B(NH4HCO3) 95 Method C, G1 1177

379.36 1H-NMR (400 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.64 (s, 1H), 8.83(s, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.38 (s,1H), 7.92 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.61 (t, J =7.8 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.32 (t, J = 74.0 Hz, 1H), 6.95(d, J = 7.2 Hz, 1H), 2.75 (s, 3H). DMSO 380.0 (M + 1) Method B (NH4HCO3)95 Method C, G1 1178

382.25 1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.62 (s, 1H), 8.86(t, J = 2.4 Hz, 1H), 8.78 (t, J = 3.2 Hz, 2H), 8.52 (d, J = 8.4 Hz, 1H),8.10-8.13 (m, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H),7.63 (t, J = 7.6 Hz, 1H), 2.75 (s, 3H). DMSO 381.9, 383.9 (M + 1) MethodB (NH4HCO3) 95 Method C, G1 1179

349.34 1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.60 (s, 1H), 8.87(s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.50-8.60 (m, 2H), 7.80-7.85 (m, 2H),7.61 (t, J = 7.8 Hz, 1H), 7.46-7.54 (m, 1H), 2.74 (s, 3H). DMSO 350.0(M + 1) Method B (NH4HCO3) 95 Method C, G1 1180

382.25 1H-NMR (400 MHz, DMSO-d6), δ 10.20 (s, 1H), 9.62 (s, 1H), 8.85(s, 1H), 8.77 (d, J = 2.8 Hz, 1H), 8.47-8.52 (m, 3H), 7.81 (d, J = 3.2Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.31 (t, J = 1.6 Hz, 1H), 2.51 (s,3H). DMSO 381.9, 383.9 (M + 1) Method B (NH4HCO3) 95 Method C, G1 1181

338.37 1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.64 (s, 1H), 8.86(d, J = 9.2 Hz, 2H), 8.78 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H),8.38 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.61-7.65 (m, 3H),2.76 (s, 3H). DMSO 339.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1 1182

383.33 1H-NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 9.99 (s, 1H), 9.41(d, J = 5.2 Hz, 1H), 8.62 (d, J = 8.4 Hz, 1H), 8.36- 8.38 (m, 1H) 8.10(s, 1H), 7.95-7.98 (m, 3H), 7.73-7.74 (m, 1H), 7.62 (t, J = 8.0 Hz, 1H),7.20 (d, J = 8.0 Hz, 1H). DMSO 384.2 (M + 1) Method B (NH4HCO3) 95Method D, G1 1183

365.34 1H-NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 10.01 (s, 1H),9.41-9.43 (m, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.39- 8.41 (m, 1H), 7.93-7.97 (m, 3H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (m, 1H), 7.54- 7 56 (m,1H), 7.32 (t, J = 74.0 Hz, 1H), 7.02-7.04 (m, 1H). DMSO 366.2 (M + 1)Method B (NH4HCO3) 95 Method D, G1 1184

398.25 1H-NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 9.96 (s, 1H), 9.44(d, J = 4.8 Hz, 1H), 8.40-8.41 (m, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.06(d, J = 2.4 Hz, 1H), 7.99-8.02 (m, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.71(d, J = 8.8 Hz, 1H), 7.56- 7.58 (m, 1H), 3.99 (s, 3H). DMSO 398.0,400.0, 402.0 (M + 1) Method B (NH4HCO3) 95 Method D, G1 1185

381.79 1H-NMR (400 MHz, DMSO-d6): δ 9.92 (s, 1H), 9.36-9.38 (m, 1H),8.27-8.29 (m, 1H), 8.14-8.16 (m, 1H), 7.51 (s, 1H), 7.83-7.91 (m, 3H),7.51-7.56 (m, 2H), 3.97 (s, 3H). DMSO 382.1, 384.1 (M + 1) Method B(NH4HCO3) 95 Method D, G1 1186

365.34 1H-NMR (400 MHz, DMSO-d6): δ 9.95- 10.00 (m, 2H), 9.40 (d, J =5.6 Hz, 1H), 8.32-8.33 (m, 1H), 8.06 (m, 1H), 7.96 (s, 1H), 7.89 (d, J =9.2 Hz, 1H), 7.69 (m, 1H), 7.54-7.59 (m, 2H), 3.98 (s, 3H). DMSO 366.1(M + 1) Method B (NH4HCO3) 95 Method D, G1 1187

354.36 1H-NMR (400 MHz, DMSO-d6): δ 10.00 (s, 1H), 9.90 (m, 1H),9.35-9.36 (m, 1H), 8.23-8.30 (m, 3H), 7.84-7.90 (m, 2H), 7.62-7.71 (m,2H), 7.54-7.57 (m, 1H), 3.96 (s, 3H). DMSO 355.1 (M + 1) Method B(NH4HCO3) 95 Method D, G1 1188

413.35 1H-NMR (400 MHz, DMSO-d6): δ 9.96- 10.0 (m, 2H), 8.39- 8.40 (m,1H), 8.31- 8.33 (m, 1H), 8.07 (s, 1H), 7.88-7.96 (m, 3H), 7.57-7.67 (m,2H), 7.22 (d, J = 8.0 Hz, 1H), 4.01 (s, 3H). DMSO 414.1 (M + 1) Method B(NH4HCO3) 95 Method D, G1 1189

373.36 1H-NMR (400 MHz, DMSO-d6): 12.15 (s, 1H), 10.02 (s, 1H), 9.41 (d,J = 5.2 Hz, 1H), 8.94 (d, J = 7.6 Hz, 1H), 8.41 (m, 1H), 8.09 (d, J =7.6 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.80 (t, J = 8.4 Hz, 1H),7.60-7.62 (m, 2H), 7.25 (t, J = 7.6 Hz, 1H), 4.01 (s, 3H). DMSO 374.1,376.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1 1190

398.25 1H-NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 9.54 (s, 1H),8.81-8.32 (m, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H),8.06 (dd, J = 8.8, 2.4 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.92 (d, J =8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H),3.40 (s, 3H). DMSO 397.9, 400.0, 401.9 (M + 1) Method B (NH4HCO3) 95Method D, G6 1191

381.79 1H-NMR (400 MHz, DMSO-d6): δ 9.90 (s, 1H), 9.52 (s, 1H), 8.81 (m,1H), 8.73 (d, J = 2.4 Hz, 1H), 8.53 (dd, J = 6.8, 2.4 Hz, 1H, 7.98- 8.03(m, 2H), 7.91 (d, J = 9.2 Hz, 1H), 7.59 (dd, J = 5.2, 2.4 Hz, 1H), 7.51(t, J = 8.8 Hz, 1H), 3.40 (s, 3H). DMSO 382.0, 384.0 (M + 1) Method B(NH4HCO3) 95 Method D, G6 1192

365.34 1H-NMR (400 MHz, DMSO-d6): δ 9.89 (s, 1H), 9.52-9.53 (m, 1H),8.81-8.82 (m, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.45-8.51 (m, 1H), 7.98 (m,1H), 7.90 (d, J = 9.2 Hz, 1H), 7.75-7.78 (m, 1H), 7.47-7.59 (m, 2H),3.40 (s, 3H). DMSO 366.0 (M + 1) Method B (NH4HCO3) 95 Method D, G6 1193

354.36 1H-NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 9.54 (s, 1H),8.74-8.81 (m, 3H), 8.35 (d, J = 8.4 Hz, 1H), 8.04 (m, 1H), 7.92-7.95 (m,1H), 7.59-7.69 (m, 3H), 3.40 (s, 3H). DMSO 355.0 (M + 1) Method B(NH4HCO3) 95 Method D, G6 1194

398.25 1H-NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 9.55 (d, J = 1.2 Hz,1H), 8.81 (t, J = 2.0 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.39 (d, J =1.6 Hz, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.59(dd, J = 8.8, 2.4 Hz, 1H), 7.32 (t, J = 1.6 Hz, 1H), 3.40 (s, 3H). DMSO398.0, 399.9, 402.0 (M + 1) Method B (NH4HCO3) 95 Method D, G6 1195

395.36 1H-NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 9.55 (m, 1H),8.74-8.79 (m, 2H), 8.25 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.92 (d, J =9.2 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 9.2, 2.4 Hz, 1H),7.48- 7.52 (m, 1H), 7.34 (t, J = 74.0 Hz, 1H), 6.96-6.98 (m, 1H), 3.40(s, 3H). DMSO 396.1 (M + 1) Method B (NH4HCO3) 95 Method D, G6 1196

377.78 1H-NMR (400 MHz, DMSO-d6): δ 12.26 (s, 1H), 9.94 (s, 1H),9.41-9.42 (m, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.33-8.34 (m, 1H), 8.19 (d,J = 8.4 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.93 (m, 1H), 7.75- 7.77 (m,2H), 7.05- 7.30 (m, 2H). DMSO 378.0, 380.0 (M + 1) Method B (NH4HCO3) 95Method D, G6 1197

343.34 1H-NMR (400 MHz, DMSO-d6): δ 13.86 (s, 1H), 12.39 (s, 1H), 9.62(d, J = 0.8 Hz, 1H), 9.29 (d, J = 8.0 Hz, 1H), 8.87 (s, 1H), 8.80 (d, J= 2.4 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.12 (dd, J = 8.0, 1.6 Hz, 1H),7.97- 8.05 (m, 3H), 7.75- 7.79 (m, 2H), 7.24 (t, J = 7.6 Hz, 1H). DMSO344.0 (M + 1) Method B (NH4HCO3) 95 Method D, G6 1198

372.38 1H-NMR (400 MHz, DMSO-d6): δ 13.05 (s, 1H), 9.99 (s, 1H), 9.39(d, J = 5.2 Hz, 1H), 9.05 (d, J = 8.4 Hz, 1H), 8.47 (s, 1H), 8.36-8.38(m, 1H), 7.85-7.98 (m, 3H), 7.71 (t, J = 7.6 Hz, 1H), 7.46- 7.60 (m,2H), 7.20 (t, J = 7.6 Hz, 1H), 3.95 (s, 3H). DMSO 373.0 (M + 1) Method B(NH4HCO3) 95 Method D, G1 1199

376.8 1H-NMR (400 MHz, DMSO-d6): δ 13.15 (s, 1H), 10.00 (s, 1H), 9.44(d, J = 4.2 Hz, 1H), 8.95 (d, J = 8.4 Hz, 1H), 8.49 (s, 1H), 8.40-8.42(m, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.91- 7.97 (m, 3H), 7.80 (t, J = 7.6Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.25 (t, J = 7.2 Hz, 1H). DMSO 377.0,379.0 (M + 1) Method B (NH4HCO3) 95 Method D, G1 1200

399.78 1H-NMR (400 MHz, DMSO-d6): δ 12.29 (s, 1H), 9.98 (s, 1H), 9.42(d, J = 5.2 Hz, 1H), 8.66 (d, J = 9.2 Hz, 1H), 8.36- 8.38 (m, 1H), 8.00(d, J = 1.5 Hz, 1H), 7.89 (s, 1H), 7.79- 7.81 (m, 2H), 7.49- 7.57 (m,1H), 7.31 (t, J = 74.0 Hz, 1H), 7.04 (dd, J = 8.0, 1.2 Hz, 1H). DMSO400.0, 401.9 (M + 1) Method A (TFA) 95 Method D, G1 1201

386.21 1H-NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 9.43 (d, J = 5.2 Hz,1H), 8.72 (d, J = 8.8 Hz, 1H), 8.33 (dd, J = 5.6, 2.4 Hz, 1H), 8.21 (dd,J = 6.4, 1.6 Hz, 1H), 7.93- 7.98 (m, 2H), 7.78 (dd, J = 8.8, 2.0 Hz,1H), 7.54 (t, J = 9.2 Hz, 2H). DMSO 386.0 387.8 (M + 1) Method A (TFA)95 Method D, G1 1202

369.76 1H-NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 9.95 (m, 1H),9.44-9.45 (m, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.32-8.34 (m, 1H),8.02-8.08 (m, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.79 (dd, J = 9.2, 2.4 Hz,1H), 7.70-7.72 (m, 1H), 7.56 (q, J = 9.2 Hz, 1H). DMSO 369.9, 371.0(M + 1) Method A (TFA) 95 Method D, G1 1203

358.78 1H-NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 9.92 (s, 1H), 9.42(d, J = 4.8 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.23- 8.33 (m, 3H), 7.96(d, J = 1.6 Hz, 1H), 7.65-7.79 (m, 3H). DMSO 359.0, 361.0 (M + 1) MethodB (NH4HCO3) 95 Method D, G1 1204

402.66 1H-NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.96 (s, 1H), 9.44(d, J = 5.2 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.28- 8.35 (m, 2H), 7.94-7.99 (m, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H). DMSO401.9, 403.9, 405.9 (M + 1) Method B (NH4HCO3) 95 Method D, G1 1205

402.66 1H-NMR (400 MHz, DMSO-d6): δ 9.90 (s, 1H), 9.42 (d, J = 4.8 Hz,1H), 8.58 (d, J = 8.8 Hz, 1H), 8.27 (s, 1H), 8.07 (s, 2H), 7.92 (s, 1H),7.73 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H). DMSO 401.9, 403.9, 405.9 (M + 1)Method B (NH4HCO3) 95 Method D, G1 1206

351.76 1H-NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 9.43 (m, 1H), 9.07(d, J = 5.2 Hz, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.50 (dd, J = 6.4, 2.0Hz, 1H), 8.31 (dd, J = 5.2, 0.8 Hz, 1H), 8.00-8.09 (m, 3H), 7.80 (t, J =7.2 Hz, 1H), 7.53 (t, J = 9.2 Hz, 1H). DMSO 352.0, 354.0 (M + 1) MethodB (NH4HCO3) 95 Method D, G1 1207

342.35 1H-NMR (400 MHz, DMSO-d6): δ 13.31 (s, 1H), 9.38-9.43 (m, 2H),9.05 (d, J = 5.2 Hz, 1H), 8.52 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.25(d, J = 8.0 Hz, 1H), 7.95-8.04 (m, 4H), 7.82 (t, J = 7.2 Hz, 1H), 7.70(t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H). DMSO 343.1 (M + 1) MethodB (NH4HCO3) 95 Method D, G1 1208

365.34 1H-NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 9.37 (d, J = 1.2 Hz,1H), 9.01 (d, J = 5.2 Hz, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.40 (dd, J =5.2, 1.2 Hz, 1H), 8.28 (t, J = 1.2 Hz, 1H), 7.92-8.00 (m, 3H), 7.77-7.79(m, 1H), 7.47-7.52 (m, 1H), 7.34 (t, J = 74.0 Hz, 1H), 6.97 (dd, J =8.4, 2.4 Hz, 1H). DMSO 366.1 (M + 1) Method B (NH4HCO3) 95 Method D, G11209

HCl (batch 02) 351.76 1H-NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 9.59(s, 2H), 9.36 (s, 1H), 8.74 (d, J = 8.4 Hz, 1H), 8.22 (dd, J = 6.8, 2.4Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.00 (t, J = 7.6 Hz, 1H), 7.90-7.94(m, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 9.2 Hz, 1H). DMSO 352.0,354.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1 1210

342.35 1H-NMR (400 MHz, DMSO-d6): δ 13.17 (s, 1H), 9.65 (s, 2H), 9.36(s, 1H), 8.93 (d, J = 8.0 Hz, 1H), 8.51 (s, 1H), 8.23 (d, J = 8.4 Hz,1H), 7.92-8.02 (m, 4H), 7.72-7.79 (m, 2H), 7.26 (t, J = 7.6 Hz, 1H).DMSO 343.1 (M + 1) Method B (NH4HCO3) 95 Method D, G4 1211

365.34 1H-NMR (400 MHz, DMSO-d6): δ 10.15 (s, 1H), 9.62 (s, 2H), 9.32(s, 1H), 8.63 (d, J = 8.0 Hz, 1H), 7.94-7.97 (m, 3H), 7.81 (dd, J = 8.4,1.2 Hz, 1H), 7.69- 7.74 (m, 1H), 7.50-7.55 (m, 1H), 7.31 (t, J = 74.0Hz, 1H), 7.01 (dd, J = 8.4, 2.4 Hz, 1H). DMSO 366.1 (M + 1) Method B(NH4HCO3) 95 Method D, G6 1212

399.78 1H-NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 10.01-10.02 (m, 1H),9.44-9.46 (m, 1H), 8.62 (d, J = 8.4 Hz, 1H), 8.40 (dd, J = 5.2, 2.0 Hz,1H), 8.04 (t, J = 1.6 Hz, 1H), 8.00 (d, J = 3.2 Hz, 2H), 7.94 (m, 1H),7.76- 7.80 (m, 1H), 7.38 (t, J = 73.8 Hz, 1H), 7.16 (t, J = 2.0 Hz, 1H).DMSO 400.0, 402.0 (M + 1) Method B (NH4HCO3) 95 Method D, G6 1213

398.79 1H-NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 9.56 (m, 1H),8.69-8.72 (m, 2H), 8.59 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H),7.94- 7.97 (m, 2H), 7.69- 7.73 (m, 1H), 7.55- 7.58 (m, 1H), 7.36 (t, J =73.6 Hz, 1H), 7.13 (t, J = 2.0 Hz, 1H). DMSO 399.0, 401.1 (M + 1) MethodB (NH4HCO3) 95 Method D, G6 1214

365.34 1H-NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 9.49 (s, 1H),8.88-8.92 (m, 3H), 8.16 (d, J = 8.0 Hz, 1H), 8.07 (t, J = 7.6 Hz, 2H),7.84 (t, J = 8.0 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.36 (t, J = 74.0Hz, 1H), 7.10-7.12 (m, 1H). DMSO 366.1 (M + 1) Method B (NH4HCO3) 95Method D, G6 1215

368.22 1H-NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 10.00 (s, 1H), 9.44(d, J = 5.2 Hz, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.38 (dd, J = 2.4, 5.2Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.96-8.00 (m, 3H) 7.73-7.77 (m, 2H).DMSO 367.8, 369.8, 371.8 (M + 1) Method B (NH4HCO3) 95 Method D, G1 1216

351.76 1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.99 (s, 1H), 9.43(d, J = 5.2 Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.38 (dd, J = 5.2, 2.0Hz, 1H), 8.22 (dd, J = 7.0, 2.6 Hz, 1H), 7.89-7.93 (m, 3H), 7.68-7.72(m, 1H), 7.55 (t, J = 8.6 Hz, 1H). DMSO 351.9, 353.8 (M + 1) Method B(NH4HCO3) 95 Method D, G1 1217

324.34 1H-NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.99 (dd, J = 2.0,1.2 Hz, 1H), 9.44 (dd, J = 5.2, 0.8 Hz, 1H), 8.61 (d, J = 8.4 Hz, 1H),8.38-8.40 (m, 2H), 8.28-8.31 (m, 1H), 7.99 (s, 1H), 7.97 (d, J = 3.6 Hz,1H), 7.66-7.80 (m, 3H). DMSO 325.0 (M + 1) Method B (NH4HCO3) 95 MethodD, G1 1218

368.22 1H-NMR (400 MHz, DMSO-d6): δ 11.94 (s, 1H), 9.44 (d, J = 0.8 Hz,1H), 9.06 (d, J = 8.0 Hz, 1H), 9.00 (d, J = 2.4 Hz, 1H), 8.97 (t, J =1.8 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.12(t, J = 7.4 Hz, 1H), 8.00 (dd, J = 8.6, 2.2 Hz, 1H), 7.86 (t, J = 7.6Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H). DMSO 367.9, 369.9, 371.8 (M + 1)Method B (NH4HCO3) 95 Method D, G6 1219

351.76 1H-NMR (400 MHz, DMSO-d6): δ 11.62 (s, 1H), 9.40 (d, J = 0.8 Hz,1H), 8.60- 8.83 (m, 3H), 8.32 (dd, J = 6.6, 2.2 Hz, 1H), 8.20 (d, J =8.8 Hz, 1H), 8.09 (t, J = 7.4 Hz, 1H), 7.95-8.00 (m, 1H), 7.85 (t, J =7.8 Hz, 1H), 7.61 (t, J = 9.2 Hz, 1H). DMSO 352.0, 354.0 (M + 1) MethodB (NH4HCO3) 95 Method D, G6 1220

335.31 1H-NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 9.48 (d, J = 0.8 Hz,1H), 8.91- 8.93 (m, 2H), 8.81 (d, J = 8.4 Hz, 1H), 8.28-8.33 (m, 1H),8.14 (d, J = 8.4 Hz, 1H), 8.06 (t, J = 7.6 Hz, 1H), 7.77- 7.85 (m, 2H),7.56- 7.63 (m, 1H) DMSO 336.1 (M + 1) Method B (NH4HCO3) 95 Method D, G61221

324.34 1H-NMR (400 MHz, DMSO-d6): δ 12.09 (s, 1H), 9.40 (d, J = 1.6 Hz,1H), 9.10 (d, J = 8.4 Hz, 1H), 9.00 (d, J = 2.0 Hz, 1H), 8.97 (t, J =2.0 Hz, 1H), 8.49 (s, 1H), 8.26-8.30 (m, 2H), 8.12-8.06 (m, 1H),7.87-7.91 (m, 1H), 7.76-7.84 (m, 2H) DMSO 324.9 (M + 1) Method B(NH4HCO3) 95 Method D, G6 1222

368.22 1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.59 (d, J = 1.2 Hz,1H), 8.85 (t, J = 1.8 Hz, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.64 (d, J =8.4 Hz, 1H), 8.42 (d, J = 1.6 Hz, 2H), 7.96-8.02 (m, 2H), 7.74-7.78 (m,1H), 7.35 (d, J = 1.6 Hz, 1H). DMSO 368.0, 370.0, 372.0 (M + 1) Method B(NH4HCO3) 95 Method D, G6 1223

368.22 1H-NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 10.00 (s, 1H), 9.45(d, J = 5.2 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.38 (dd, J = 5.0, 1.8Hz, 1H), 8.09 (s, 2H), 7.94 (s, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.70-7.74(m, 1H), 7.35 (s, 1H). DMSO 368.1, 370.1 (M + 1) Method B (NH4HCO3) 95Method D, G1 1224

413.81 1H-NMR (400 MHz, DMSO-d6): δ 10.05 (s, 1H), 9.63 (s, 1H), 8.82(s, 1H), 8.78 (s, 1H), 8.66 (s, 1H), 8.31 (s, 1H), 7.89- 7.91 (m, 2H),7.49 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 73.6 Hz, 1H), 6.96 (d, J = 7.6Hz, 1H), 2.74 (s, 3H). DMSO 414.0 416.0 (M + 1) Method B (NH4HCO3) 95Method C, G3 1225

400.24 1H NMR (400 MHz, DMSO-d6): δ 9.90 (s, 1H), 9.54 (s, 1H),8.77-8.80 (m, 2H), 8.60 (s, 1H), 8.50 (s, 1H), 7.99 (s, 1H), 7.76 (8,1H), 7.44 (s, 1H), 2.67 (s, 3H). DMSO 400.0 401.9 (M + 1) Method B(NH4HCO3) 95 Method C, G3 1226

390.83 1H-NMR (400 MHz, DMSO-d6): δ 13.33 (s, 1H), 9.67 (s, 1H), 9.38(d, J = 8.0 Hz, 1H), 8.88 (s, 1H), 8.79 (s, 1H), 8.52 (s, 1H), 8.08 (s,1H), 8.04 (s, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.88 (s, 1H), 7.69 (d, J =7.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 2.75 (s, 3H). DMSO 391.0 392.0(M + 1) Method A (TFA) 95 Method C, G3 1227

391.81 1H-NMR (400 MHz, DMSO-d6): δ 16.00 (s, 1H), 9.69 (s, 1H), 9.39(d, J = 8.4 Hz, 1H), 8.90 (s, 1H), 8.79 (s, 1H), 8.29 (s, 1H), 8.13 (d,J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.50 (s, J = 7.6 Hz, 1H), 7.06 (t, J =7.2 Hz, 1H), 2.73 (s, 3H). DMSO 392.0 393.1 (M + 1) Method A (TFA) 95Method C, G3 1228

372.81 1H-NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 9.57 (s, 1H), 8.82(s, 2H), 8.76 (s, 1H), 8.57 (s, 1H), 8.32 (d, J = 7.6 Hz, 1H), 7.81 (s,1H), 7.57-7.63 (m, 2H), 2.70 (s, 3H). DMSO 373.0 374.0 (M + 1) Method B(NH4HCO3) 95 Method C, G3 1229

416.69 1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 9.63 (d, J = 1.2 Hz,1H), 8.85 (dd, J = 2.4, 1.6 Hz, 1H), 8.78 (d, J = 2.4 Hz, 2H), 8.63 (d,J = 1.6 Hz, 1H), 8.45 (s, 2H), 7.34 (t, J = 2.0 Hz, 1H), 2.74 (s, 3H).DMSO 416.9 417.9 (M + 1) Method B (NH4HCO3) 95 Method C, G3 1230

HCl 351.76 1H-NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.60 (s, 2H),9.34 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.24 (dd, J = 8.4, 2.4 Hz, 1H),7.98- 7.92 (m, 3H), 7.76- 7.71 (m, 1H), 7.56 (t, J = 8.8 Hz, 1H). DMSO352.0, 354.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1 1231

HCl 383.33 1H-NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 9.61 (s, 2H),9.34 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 8.04- 7.93 (m,3H), 7.78- 7.73 (m, 1H), 7.62 (t, J = 8.4 Hz, 1H), 7.21 (d, J = 8.0 Hz,1H). DMSO 384.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1 1232

421.25 1H-NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.58 (s, 1H),9.27-9.25 (m, 1H), 8.84-8.77 (m, 2H), 9.52 (s, 1H), 8.35 (s, 1H),8.07-7.67 (m, 5H), 7.20 (t, J = 7.5 Hz, 1H). DMSO 421.0, 423.0 (M + 1)Method B (NH4HCO3) 95 Method C, G6 1233

1H-NMR (400 MHz, DMSO-d6): δ 13.15 (s, 1H), 10.00 (s, 1H), 9.44 (d, J =5.2 Hz, 1H), 8.95 (d, J = 8.4 Hz, 1H), 8.48 (s, 1H), 8.42-8.40 (m, 1H),8.16 (d, J = 9.2 Hz, 1H), 7.97- 7.91 (m, 3H), 7.81- 7.73 (m, 2H), 7.25(t, J = 2.4 Hz, 1H). DMSO 377.0 (M + 1) Method B (NH4HCO3) 95 Method G1234

1H-NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 9.54 (s, 1H), 8.82 (s, 1H),8.74 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.07 (dd, J = 8.8,2.4 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.70(d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H), 4.00 (s, 3H). DMSO397.9, 400.0 (M + 1) Method B (NH4HCO3) 95 Method G

Method C: 5-Nitro-2-(pyrazine-2-carboxamido)benzoic acid (Ii-a)

To a solution of pyrazine-2-carboxylic acid (1.36 g, 10.9 mmol, 1 eq.)in SOCl₂ (20 mL) was added DMF (2 drops). The mixture was stirred at 60°C. for 2.0 min. The volatiles were removed in vacuo to give crudepyrazine-2-carbonyl chloride, which was used in the next step directly.TO a suspension of 2-amino-5-nitrobenzoic acid (2.00 g, 10.9 mmol, 1.0eq.) in THF (50 mL) was added Et₃N (1.09 g) and pyrazine-2-carbonylchloride in anhydrous THF (50 mL) dropwise. The resulting mixture wasstirred at room temperature for 18 h. After the reaction was completed,the volatiles were removed. The residue was suspended in H₂O (10 mL) andthe pH was adjusted to 5 by slow addition of 2N HCl in water. Theresulting solid was collected and dried in vacuo to give 3.12 g of5-nitro-2-(pyrazine-2-carboxamido)benzoic acid as a brown solid (99%).LCMS m/z=289.0 (M+1) (Method B) (retention time=1.24 min),

Method A: N-(2-carbamoyl-4-nitrophenyl)pyrazine-2-carboxamide (iii-d)

A mixture of 5-nitro-2-(pyrazine-2-carboxamido)benzoic acid (3.12 g,10.8 mmol) in SOCl₂ (20 mL) was stirred at 80° C. for 2 h. Aftercooling, the volatiles were removed and the residue was suspended in DCM(150 mL), and a solution of NH₃.H₂O (25% by weight water, 40 mL) wasadded and stirred for 4 h. The resulting precipitate was collected anddried in vacuo to give 2.42 g ofN-(2-carbamoyl-4-nitrophenyl)pyrazine-2-carboxamide as a dark red solid(74.6). LCMS m/z=288.0 (M+1) (Method B) (retention time=1.11 min).

Method E2: 6-nitro-2-(pyrazin-2-yl)quinazolin-4(1H)-one (iv-g)

To a mixture of N-(2-carbamoyl-4-nitrophenyl)pyrazine-2-carboxamide(2.42 g, 8.43 mmol, 1.0 eq.) in EtOH (60 mL) was added NaOH (198 g, 49.5mmol, 5.0 eq.). The resulting mixture was stirred at room temperaturefor 18 h. After the reaction was completed, the volatiles were removedin vacuo. The residue was partitioned between H₂O (50 mL) and ethylacetate (50 mL). The aqueous layer was neutralized to pH 5 by slowaddition of aqueous citric acid. The resulting precipitate was collectedand dried to give 2.00 g of 6-nitro-2-(pyrazin-2-yl)quinazolin-4(3H)-oneas a yellow solid (88%), LCMS m/z=270.1 (M+1) (Method A) (retentiontime=1.36 min).

Method F2: 4-Chloro-6-nitro-2-(pyrazin-2-yl)quinazoline (v-g)

To a mixture of 6-nitro-2-(pyrazin-2-yl)quinazolin-4(3H)-one (1.00 g,3.7 mmol) in POCl₃ (10 mL) was added N,N-dimethylbenzenamine (0.1 mL).The resulting mixture was stirred at 120° C. for 2 h. After the reactionwas completed, POCl₃ was removed in vacuo, and the residue wasco-evaporated with toluene twice to give a dark crude product, which wasused for the next step without further purification.

Method G6:N-(3-(difluoromethoxy)phenyl)-6-nitro-2-(pyrazin-2-yl)quinazolin-4-amine(vi-s)

A mixture of 4-chloro-6-nitro-2-(pyrazin-2-yl)quinazoline (1.00 g,crude, 3.7 mmol, 1.0 eq.), 3-(difluoromethoxy)benzenamine (600 mg, 3.7mmol, 1.0 eq.) and Et₃N (1.00 g, 10 mmol, 3.0 eq) in THF (80 mL) wasstirred at 75° C. for 18 h. After cooling, the volatiles were removed invacuo and the residue was washed with H₂O (100 mL×2). The solid wasdried in vacuo to afford 1.40 g ofN-(3-(difluoromethoxy)phenyl)-6-nitro-2-(pyrazin-2-yl)quinazolin-4-amineas a black solid (90.2% of two steps). LCMS m′ z=411.0 (M+1) (Method A)(retention time=1.61 min).

Method B:N⁴-(3-(difluoromethoxy)phenyl)-2-(pyrazin-2-yl)quinazoline-4,6-diamine(Iii-a)

To a mixture of N-(3-(difluoromethoxy)phenyl)-6-nitro-2-(pyrazin-2-yl)quinazolin-4-amine (1.40 g, 3.4 mmol, 1.0 eq.) in MeOH-H₂O (v/v, 3:1,110 mL) was added NH₄Cl (1.80 g, 34 mmol, 10.0 eq.) and Fe (1.91 g, 34mmol, 10.0 eq.). The resulting mixture was stirred at 60° C. for 3 h.After the reaction was completed, the mixture was cooled to roomtemperature, and the iron was filtered off. The filtrate wasconcentrated to 15 ml, and a precipitate formed and was collected anddried in vacuo to give 1.13 g ofN⁴-(3-(difluoromethoxy)phenyl)-2-(pyrazin-2-yl)quinazoline-4,6-diamineas a pale yellow solid (87.5%). LCMS m/z=381.1 (M+1) (Method B)(retention time=1.60 min), ¹H-NMR (400 MHz, DMSO-d₆): δ 9.69 (s, 1H),9.52 (d, J=1.2 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H),8.30 (s, 1H), 7.87 (dd, J=8.4, 0.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H),7.49-7.42 (m, 2H), 7.33-7.32 (m, 1H), 7.31 (t, J=7.4 Hz, 1H), 5.85 (s,2H).

Method C:N-(4-(3-(difluoromethoxy)phenylamino)-2-(pyrazin-2-yl)quinazolin-6-yl)-6-methoxynicotinamide(liii-a)

To a solution of 6-methoxynicotinic acid (100 mg, 0.65 mmol) in SOCK, (2mL) was added DMF (1 drop). The mixture was stirred at 60° C. for 20min. The volatiles were removed in vacuo to give 6-methoxynicotinoylchloride, which was used for the next step directly. To a suspension ofN⁴-(3-(difluoromethoxy)phenyl)-2-(pyrazin-2-yl)quinazoline-4,6-diamine(130 mg, 0.34 mmol, 0.5 eq.) in THF (5 mL) and Et₃N (101 mg, 1 mmol, 3.0eq) was added 6-methoxynicotinoyl chloride in anhydrous THF (5 mL)dropwise. The resulting mixture was stirred at room temperature for 18h. The volatiles were removed in vacuo. The residue was washed with MeOHand re-crystallized from THF/MeOH twice, and purified by reverse phasechromatography PREP-HPLC (A=NH₄HCO₃—H₂O, 10 mmol/L, B=MeOH) to afford 33mg ofN-(4-(3-(difluoromethoxy)phenylamino)-2-(pyrazin-2-yl)quinazolin-6-yl)-6-methoxynicotinamideas a pale yellow solid (18.8%). LCMS m/z=516.1 (M+1), 258.6 (M/2+1)(Method A) (retention time=1.57 min), ¹H-NMR (400 MHz, DMSO-(d₆): δ10.71 (s, 1H), 10.18 (s, 1H), 9.57 (d, J=1.6 Hz, 1H), 9.01 (d, J=1.6 Hz,1H), 8.91 (d, J=2.4 Hz, 1H), 8.81 (t, J=2.0 Hz, 1H), 8.76 (d, J=2.4 Hz,1H), 8.34 (dd, J=8.8, 2.8 Hz, 1H), 8.23 (s, 1H), 8.08 (dd, J=8.8, 2.0Hz, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.46-7.50 (m,1H), 7.32 (t, J=74.4 Hz 1H), 7.02 (d, J=8.8 Hz, 1H), 6.95 (dd, J=8.0,2.0 Hz, 1H), 3.97 (s, 3H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 67 (prepared according to method procedureA-G as designated).

TABLE 22 Molec- Salt ular Number PRODUCT type Mass ¹H-NMR 1242

422.39 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.10- 10.45 (m, 2H), 9.68 (s, 1H),8.45-9.10 (m, 2H), 7.68-8.37 (m, 4H), 7.36-7.52 (m, 2H), 7.02- 7.08 (m,1H), 2.21 (s, 3H). 1243

515.47 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.71 (s, 1H), 10.18 (s, 1H), 9.57(d, J = 1.6 Hz, 1H), 9.01 (d, J = 1.6 Hz, 1H), 8.91 (d, J = 2.4 Hz, 1H),8.81 (t, J = 2.0 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.34 (dd, J = 8.8,2.8 Hz, 1H), 8.23 (s, 1H), 8.08 (dd, J = 8.8, 2.0 Hz, 1H), 8.00 (d, J =9.2 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.46-7.50 (m, 1H), 7.32 (t, J =74.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.95 (dd, J = 8.0, 2.0 Hz, 1H),3.97 (s, 3H). 1244

514.48 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 10.16 (s, 1H), 9.57(s, 1H), 9.00 (d, J = 1.6 Hz, 1H), 8.81(d, J = 2.4 Hz, 1H), 8.76 (d, J =2.8 Hz, 1H), 8.23 (s, 1H), 8.07-8.12 (m, 3H), 7.99 (d, J = 9.2 Hz, 1H),7.89 (d, J = 9.2 Hz, 1H), 7.46-7.50 (m, 1H), 7.32 (t, J = 72.8 Hz, 1H),7.11- 7.13 (m, 2H), 6.95 (dd, J = 8.4, 2.4 Hz, 1H), 3.87 (s, 3H). 1245

520.53 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.30 (s, 1H), 10.16 (s, 1H), 9.54(s, 1H), 8.89 (s, 1H), 8.79 (t, J = 2.4 Hz, 1H), 8.74 (d, J = 2.8 Hz,1H), 8.20 (s, 1H), 7.93 (s, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.48 (dd, J =10.0, 2.0 Hz, 1H), 7.31 (t, J = 74.0 Hz, 1H), 6.94 (dd, J = 8.4, 2.0 Hz,1H), 3.26 (s, 3H), 3.18-3.22 (m, 1H), 1.91-1.96 (m, 2H), 1.66- 1.78 (m,2H), 1.53-1.63 (m, 2H), 1.38-1.49 (m, 2H). 1246

492.48 ¹H-NMR (400 MHz, DMSO-d₆): δ 10.35 (s, 1H), 10.15 (s, 1H), 9.54(s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.80 (dd, J = 2.4, 1.2 Hz, 1H), 8.75(d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.86-7.91(m, 2H), 7.48 (dd, J = 10.8, 2.8 Hz, 1H), 7.31 (t, J = 74.4 Hz, 1H),6.94 (dd, J = 7.6, 2.0 Hz, 1H), 3.94-3.97 (m, 2H), 3.40-3.43 (m, 2H),2.70-2.73 (m, 1H), 1.65-1.78 (m, 4H). ¹H-NMR LCMS Purity Method forNumber Solvent LCMS Protocol percent Coupling 1242 DMSO 423.0 (M + 1)Method A (TFA) 95 Method C, G4, C 1243 DMSO 516.2 (M + 1) Method B(NH4HCO3) 95 Method C, G4, C 1244 DMSO 515.2 (M + 1) Method B (NH4HCO3)95 Method C, G4, C 1245 DMSO 521.2 (M + 1) Method B (NH4HCO3) 95 MethodC, G4, C 1246 DMSO 493.2 (M + 1) Method B (NH4HCO3) 95 Method C, G4, C

Method BF:6-(3-methoxyphenyl)-N-methy-2-(pyrimidin-5-yl)quinazolin-4-amine(compound 1247)

In a 10 mL microwave vial was added2-chloro-6-(3-methoxyphenyl)-N-methylquinazolin-4-amine (0.080 g, 0.267mmol), pyrimidine-5-boronic acid (0.099 g, 0.801 mmol),dichlorobis(triphenylphosphine)palladium (II) (Pd(PPh₃)₂Cl₂) (9.37 mg,0.013 mmol), and potassium carbonate (0.111 g, 0.801 mmol) in DME (3mL), EtOH (1.286 mL), and water (0.857 mL) to give a yellow suspension.The vial was irradiated at 120° C. for 15 min under argon. Water (10rill) was added to the mixture and extracted with ethyl acetate (2×10mL). The organic layers were combined and washed with brine (1×20 mL)and then dried over MgSO₄, filtered and concentrated. The residue waswashed with MeOH-CH₂Cl₂ and dried to give 35 mg of6-(3-methoxyphenyl)-N-methyl-2-(pyrimidin-5-yl)quinazolin-4-amine as awhite solid (38%). LCMS m/z=344 (M+1) (Method D) (retention time=1.78min) ¹H NMR (300 MHz, DMSO) δ 9.79-9.59 (m, 2H), 9.30 (s, 1H), 8.72 (d,J=4.6 Hz, 1H), 8.59 (s, 1H), 8.16 (d, J=8.6 Hz, 1H), 7.85 (d, J=8.7 Hz,1H), 7.53-7.28 (m, 3H), 7.00 (d, J=6.8 Hz, 1H), 3.86 (s, 3H), 3.18 (d,J=3.9 Hz, 3H).

In a 100 mL round-bottomed flask was added6-iodo-2-(pyrazin-2-yl)quinazolin-4(3H)-one (0.500 g, 1.428 mmol), BOP(0.821 g, 1.857 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.426 ml,2.86 mmol) in DMT (10 mL) to give a colorless solution. Methylamine, 2Min THF (2.142 ml, 4.28 mmol) was added and stirred at room temperatureovernight. The reaction mixture was diluted with water (50 mL) and thena precipitate formed. The resulting solid was collected by filtrationand dried to give 0.515 g of6-iodo-N-methyl-2-(pyrazin-2-yl)quinazolin-4-amine as a pale brown solidin a 99% yield. LCMS m/z=364 (M+1) (Method D) (retention time=1.25 min).¹H NMR (300 MHz, DMSO) δ 9.60 (s, 1H), 8.89-8.65 (m, 3H), 8.65-8.48 (m,1H), 8.06 (d, J=8.7 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 3.11 (d, J=4.2 Hz,3H).

In a 50 ml, round-bottomed flask was added6-iodo-N-methyl-2-(pyrazin-2-yl)quinazolin-4-amine (0.100 g, 0.275mmol), 3-methoxyphenylboronic acid (0.063 g, 0.413 mmol),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II)(0.016 g, 0.022 mmol), and potassium phosphate tribasic monohydrate(0.190 g, 0.826 mmol) in dioxane (5 mL) and water (0.5 mL) to give abrown suspension. The reaction mixture was heated at 80° C. overnightunder argon. After cooling to room temperature, the reaction mixture wasdiluted with water (10 mL) and then a precipitate formed. The resultingsolid was collected by filtration and washed with ethyl acetate anddried to give 25 mg of6-(3-methoxyphenyl)-N-methyl-2-(pyrazin-2-yl)quinazolin-4-amine as apale yellow solid in a 26% yield. LCMS m/z=344 (M+1) (Method D)(retention time=1.43 ruin). ¹H NMR (300 MHz, DMSO) δ 9.64 (s, 1H),8.85-8.78 (m, 1H), 8.77-8.71 (m, 1H), 8.70-8.63 (m, 1H), 8.63-8.55 (m,1H), 8.18 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.9 Hz, 1H), 7.53-7.31 (m, 3H),7.09-6.92 (m, 1H), 3.86 (5, 3H), 3.17 (d, J=3.6 Hz, 3H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 69 (prepared according to method describedfor 6-(3-methoxyphenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine).

TABLE 23 Molec- Salt ular Number PRODUCT type Mass ¹H-NMR 1235

343.38 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.85-8.78 (m, 1H),8.77-8.71 (m, 1H), 8.70-8.63 (m, 1H), 8.63- 8.55 (m, 1H), 8.18 (d, J =0.8 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.53-7.31 (m, 3H), 7.09-6.92 (m,1H), 3.86 (s, 3H), 3.17 (d, J = 3.6 Hz, 3H). 1236

338.37 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.87-8.61 (m, 4H), 8.24(d, J = 8.8 Hz, 1H), 8.15-7.98 (m, 4H), 7.92 (d, J = 8.7 Hz, 1H), 3.17(d, J = 4.0 Hz, 3H). 1237

2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 10.17 (s, 1H), 9.54 (d, J = 5.2 Hz,1H), 9.36 (s, 1H), 8.63 (s, 2H), 8.13- 8.06 (m, 2H), 7.58-7.51 (m, 2H),7.43-7.38 (m, 1H), 3.23 (d, J = 4.0 Hz, 3H). 1238

2HCl ¹H-NMR (400 MHz, DMSO- 10.14 (s, 1H), 9.50 (d, J = 5.2 Hz, 1H),9.24 (s, 1H), 8.60 (dd, J = 5.4, 1.8 Hz, 1H), 8.55 (s, 1H), 8.04 (q, J =8.8 Hz, 2H), 7.76 (dd, J = 15.4, 9.0 Hz, 1H), 7.51-7.45 (m, 1H), 7.32(dt, J = 8.4, 2.0 Hz, 1H), 3.23 (d, J = 4.4 Hz, 3H). 1239

¹H-NMR (400 MHz, DMSO-d₆): δ 9.73 (s, 1H), 9.32 (s, 1H), 8.74 (d, J =4.4 Hz, 1H), 8.51 (s, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 8.6Hz, 1H), 7.54- 7.49 (m, 2H), 7.42-7.37 (m, 1H), 4.12 (q, J = 5.2 Hz,1H), 3.17 (t, J = 4.5 Hz, 3H). 1240

2HCl ¹H-NMR (400 MHz, CD3OD): δ 9.77 (s, 1H), 8.85 (d, J = 11.4 Hz, 2H),8.42 (s, 1H), 8.19-8.03 (m, 2H), 7.60 (dd, J = 15.6, 7.8 Hz, 1H), 7.10(t, J = 8.4 Hz, 2H), 3.38 (s, 3H). 1241

2HCl ¹H-NMR (400 MHz, DMSO): δ 10.84 (d, J = 1.8 Hz, 1H), 9.87 (s, 1H),9.06 (d, J = 13.6 Hz, 2H), 8.90 (s, 1H), 8.32 (t, J = 9.8 Hz, 2H),7.67-7.35 (m, 3H), 3.39 (s, 3H). ¹H-NMR LCMS Purity Method for NumberSolvent LCMS Protocol percent Coupling 1235 DMSO 344 (M + 1) Method D100 Method AP/AQ 1236 DMSO 339 (M + 1) Method D 100 Method C, G1 1237DMSO 350.1, 351.1, (M + 1) Method B (NH₄HCO₃) 95 Method C, G1 1238 DMSO350.1, 351.1, (M + 1) Method B (NH₄HCO₃) 95 Method C, G1 1239 DMSO 350.1(M + 1) Method B (NH₄HCO₃) 95 Method C, G1 1240 CD3OD 350.1 (M + 1)Method B (NH₄HCO₃) 95 Method C, G1 1241 DMSO 349.9 (M + 1) Method B(NH₄HCO₃) 95 Method C, G1

Method B2: 2-Amino-3-methylbenzoic acid (Iv-a)

Pd/C catalyst (ISO mg) was suspended in a solution of3-methyl-2-nitrobenzoic acid (1.50 g, 8.28 mmol, 1.0 eq) in THF (60 mL),the mixture was stirred under H₂ atmosphere at room temperatureovernight. The Pd/C was removed by filtration over Celite and the THFwas removed in vacuo to give 1.23 g of Iv-a as a white solid (yield98%). LCMS m/z=152.1 (M+1) (Method B) (retention time=0.73 min). Theproduct was used further without purification.

Method AZ: 2-Amino-5-bromo-3-methylbenzoic acid (Ivi-a)

To a solution of 2-amino-3-methylbenzoic acid (1.23 g, 8.14 mmol, 1.0eq) in 15 mL of DMSO was added 40% HBr (6.00 mL, 44.7 mmol, 5 eq). Theresulting mixture was stirred at room temperature overnight. A whiteprecipitate formed during the course of the reaction. The reactionmixture was quenched with saturated aqueous NaHCO₃ resulting in a whitesolid that was filtered and dried in vacuo to yield 950 mg in 51% yieldof Ivi-a as white solid. LCMS m/z=229.9 (M+1) (Method B) (retentiontime=1.20 min),

Method C: 2-Amino-5-bromo-3-methylbenzamide (ii-e)

A mixture of 2-amino-5-bromo-3-methylbenzoic acid (950 mg, 4.15 mmol)and SOCl₂ (20 mL) was stirred at 80° C. for 2 h. After the reaction wascompleted, the mixture was cooled to room temperature. The SOCl₂ wasremoved in vacuo and the residue was dissolved in anhydrous THF (10 mL).The THF solution was then added dropwise to a 28% by weight solution ofNH₃—H₂O (10 mL). After 1 h, the resulting precipitate was collected anddried in vacuo to give 82.0 mg of ii-c as a yellow solid (87%). LCMSm/z=288.9, 230.9 (M+1) (Method B) (retention time=1.49 min).

Method G for Coupling ConditionsG1: i-PrOH/85-100° C.G2: THF/heatG3: i-AmOH/100-130° C.G4: MeOH/microwave/150° C.G5: i-AmOH/microwave/150° C.G6: THF/Et₃N/refluxG7: THF-H₂O/NaOAc/rt-60° C.G8: NaH/THFG9: n-BuLi/THFG10: LHMDS/THFG11: LDA/THFG13: Cs₂CO₃/DMA/80° C.G14: NaOtBu/DMF/Microwave/100° C.Method AQ for Coupling ConditionsAQ1: Pd(PPh₃)₂Cl₂/K₂CO₃/Dioxane-H₂OAQ2: Pd₂(APhos)₂Cl₂/K₃PO₄/Dioxane-H₂OAQ3: Pd(PPh₃)₄/K₃PO₄/Dioxane-H₂OAQ4: Pd(dppf)Cl₂—CH₂Cl₂/K₃PO₄/Dioxane-H₂OAQ5: Pd(OAc)₂Cl₂/S-Phos/K₃PO₄/Dioxane-H₂OAQ6: Pd(dppf)Cl₂—CH₂Cl₂/Na₂CO₃/Dioxane-H₂O

Method C: N-(4-bromo-2-carbamoyl-6-methylphenyl)nicotinamide (iii-e)

To a solution of 2-amino-5-bromo-3-methylbenzamide (820 mg, 3.55 mmol,1.0 eq.) in THF (15 mL) and Et₃N (0.7 nit) was added nicotinoyl chloride(551 mg, 3.91 mmol, 1.1 eq.) in anhydrous THF (15 mL) dropwise. Theresulting mixture was stirred at room temperature overnight. After thereaction was completed, the resultant precipitate was filtered and driedin vacuo to give 1.74 g of crude iii-e as a yellow solid. LCMSm/z=333.8, 335.8 (M+1) (Method B) (retention time=1.42 min).

Method E: 6-Bromo-8-methyl-2-(pyridin-3-yl)quinazolin-4-ol (iv-h)

A mixture of N-(4-bromo-2-carbamoyl-6-methylphenyl)nicotinamide (1.74 gsalt, 5.22 mmol, 1.0 eq) in EtOH (50 mL) was treated with NaOH (1.04 g,26.1 mmol, 5.0 eq). The resulting mixture was stirred at roomtemperature overnight. After the reaction was completed, the volatileswere removed in vacuo. Water (30 mL) was added to the residue and themixture was adjusted to pH˜1 or 2 by slow addition of aqueous HCl. Theresultant precipitate was collected and dried to give 870 mg of iv-h asa yellow solid (77% yield after two steps), LCMS m/z=315.7, 317.7 (M+1)(Method B) (retention time=1.74 min).

Method F5: 6-Bromo-4-chloro-8-methyl-2-(pyridin-3-yl)quinazoline (v-h)

6-Bromo-8-methyl-2-(pyridin-3-yl)quinazolin-4-ol (870 mg, 2.76 mmol) wasadded POCl₃ (10 mL). The resulting mixture was stirred at 120° C.overnight. After the reaction was completed, the mixture was carefullypoured into ice-water. The pH was adjusted to 7 by slow addition ofNH₄OH at 0° C. The resultant solid was collected to give 1.00 g of v-has a beige solid (quantitative yield). LCMS m/z=333.9, 335.9 (M+1)(Method B) (retention time=2.23 min).

Method G6: 6-Bromo-N, 8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine(vi-t)

A mixture of 6-bromo-4-chloro-8-methyl-2-(pyridin-3-yl)quinazoline (200mg, 0.60 mmol, 1.0 eq.), methylamine (81 mg, 1.20 mmol, 2.0 eq.) andEt₃N (0.2 mL) in i-PrOH (10 mL) was stirred at 85° C. overnight. Theresultant yellow precipitate was collected to afford 125 mg of vi-t as abeige solid (63.4%). LCMS m/z=328.8, 330.8 (M+1-1) (Method B) (retentiontime=1.95 min).

Method G2: 7-bromo-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (vi-u)

To a suspension of 7-bronco-4-chloro-2-(pyridin-3-yl)quinazoline (5.0 g,0.0156 mol) in THF (100 mL) was added dropwise a methylamine solution(40 wt. % in H₂O) (24 ml, 0.272 mmol) with cooling. The suspension wasstirred at 60° C. for 3 h, cooled, filtered, and dried to give the titlecompound. (3.62 g, 73.5%)

Method AQ1:6-(3-Methoxyphenyl)-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine(Iviii-a)

(This method is representative of method AQ2 and can be implemented in asimilar way except for substitution of the appropriate catalyst andbase) To a mixture of6-bronco-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (130 mg, 0.396mmol, 1.0 eq), 3-methoxyphenylboronic acid (60 mg, 0.396 mmol, 1.0 eq),K₂CO₃ (295 mg, 2.14 mmol, 5.4 eq.) in dioxane (8 mL) and H₂O (4 mL) wasadded Pd(PPh₃)₂Cl₂ (15 mg, 0.021 mmol, 0.054 eq) under N₂ atmosphere.The resulting mixture was stirred at 120° C. under N₂ atmosphereovernight. After the reaction was completed, the mixture was filtered,and the filtrate was concentrated in vacuo. The residue was purified byreverse phase HPLC column to afford 11 mg of Iviii-a as a white solid(yield 7.8%). LCMS m/z=357.2, (M+1) (Method B (retention time=2.11 min),¹H NMR (400 MHz, DMSO-d₆): δ 9.68 (d, J=1.2 Hz, 1H), 8.75 (d, J=8.0 Hz,1H), 8.62 (d, J=4.6 Hz, 1H), 8.49 (d, J=4.4 Hz, 1H), 8.35 (s, 1H), 7.97(s, 1H), 7.49 (dd, J=7.8, 4.8 Hz, 1H), 7.44-7.29 (m, 3H), 6.93 (dd,J=6.8, 2.4 Hz, 1H), 3.81 (s, 3H), 3.12 (d, J=4.4 Hz, 3H), 2.68 (s, 3H).

Method AQ3:6-(4-Fluorophenyl)-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-aminedihydrochloride (Iviii-h)

6-Bromo-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (340 mg, 1.03mmol), 3-fluorobenzeneboronic acid (217 mg, 1.55 mmol), K₂PO₄ (658 mg,3.10 mmol) and Pd(PPh₃)₄ (59.7 mg, 0.052 mmol) were dissolved in themixed solvent of 1,4-dioxane (10 mL) and water (1 mL). The resultingmixture was stirred at 90° C. for 6 hours under a nitrogen atmosphere.After the reaction was completed, water was added to the mixture andstirred for 30 minutes. The resulting precipitate was collected byfiltration and purified by column chromatography on NH-silica gel(eluted with THF) to give a yellow powder. The solid was suspended inethanol and 5N HCl (1 mL) was added to the mixture. The mixture wassonicated for 10 min and the resulting precipitate was collected byfiltration and dried to give 304 mg of6-(3-fluorophenyl)-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4 aminedihydrochloride as a yellow powder in 71% yield.

Method AQ4:6-(2,4-Difluorophenyl)-N,5-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine(Iviii-c)

6-Bromo-N,5-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (350 mg, 1.06mmol), 2,4-difluorophenylboronic acid (252 mg, 1.595 mmol), K₃PO₄ (677mg, 3.19 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (87 mg, 0.106 mmol) were dissolvedin the mixed solvent of 1,4-dioxane (10 mL) and water (1 mL). Theresulting mixture was stirred at 90° C. for 2.5 hours under N₂. Afterthe reaction was completed, water was added to the mixture and extractedwith ethyl acetate. The combined organic layers were washed with waterand brine, dried over Na₂SO₄. After filtration and evaporation, thecrude product was purified by column chromatography on NH-silica gel(eluted with isocratic 33% ethyl acetate/67% hexane) to give a whitepowder. The solid was suspended in ethanol and 5N HCl (1.0 mL) was addedto the mixture. The mixture was sonicated for 10 min and the resultantprecipitate was collected by filtration and dried to give 139 mg of6-(2,4-difluorophenyl)-N,5-dimethyl-2-(pyridin-3-yl)quinazolin-4-aminedihydrochloride as a pale yellow powder in a 30% yield.

Method AQ5:7-(3-fluorophenyl)-N,6-dimethyl-2-(pyridin-3-yl)quinazolin-4-aminedihydrochloride (Iviii-d)

A mixture of 7-chloro-N,6-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine(400 mg, 1.40 mmol), 3-fluorophenylboronic acid (294 g, 2.10 mmol),Pd(OAc) (15.8 mg, 0.070 mmol),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (86.7 mg, 0.211 mmol),K₃PO₄ (900 mg, 4.23 mmol) in dioxane (10 mL) and water (2 mL) wasstirred under reflux for 2.5 h. Ethyl acetate (20 mL) was added to thecooled mixture and a precipiate formed and was filtered. The solid wasrecrystallized from DMF and water to give the title compound as freeform. The solid was suspended in ethyl acetate (10 mL) and 4N HCl inethyl acetate (1.0 mL) was added. The resulting solid was subjected tosonication for 20 min, filtered and dried to give the title compound asthe bis-110 salt (0.10 g, 18.7%).

MethodAQ6:7-(3,4-difluorophenyl)-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-aminedihydrochloride (Iviii-e)

To a suspension of 3,4-difluorophenylboronic acid (389 mg, 2.46 mmol)and 7-bromo-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (395.4 mg,1.201 mmol) in dioxane/H₂O (2/1) (30 mL) under a nitrogen atmosphere wasadded Na₂CO₃ (633.2 mg, 5.97 mmol) and(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (98 mg,0.120 mmol) at room temperature. The mixture was stirred at 100° C. for1.5 h. Water was added to the reaction mixture and then a precipitateformed. The solid was filtered and washed with water and dried. Thedried solid was then heated in a methanol/dioxane mixture to give aclear solution and filtered through Celite. The filtrate wasconcentrated to give the crude product. The crude product was sonicatedin methanol/CH₂Cl₂ for ca. 15 min and filtered to give 305.2 mg of apale brown solid as the parent compound. To a suspension of parentcompound in methanol was added 4N HCl in ethyl acetate (ca. 4 mL) togive a clear solution. The solution was concentrated and recrystallizedfrom ethanol to give the HCl salt. The salt was collected and dried inan oven at 60° C. to give 231.3 mg in a 44% yield as pale yellow solid.¹H NMR (DMSO-d₆) δ 9.73 (s, 1H), 9.37 (brd, J=8.08 Hz, 1H), 8.97 (brd,J=5.24 Hz, 1H), 8.77 (brs, 1H), 8.20 (d, J=8.48 Hz, 1H), 8.10-8.07 (brm,1H), 7.63-7.55 (brm, 2H), 7.47 (d, J=8.48 Hz, 1H), 7.32 (brm, 1H), 3.20(d, J=4.20 Hz, 3H), 2.65 (s, 3H). The 1H of 2HCl was not observed.

Method AP: 6-bromo-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine (vi-u)

To a solution of 6-promo-2-(pyridin-3-yl)quinazolin-4(3H)-one (5.00 g,16.6 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (BOP) (9.52 g, 21.5 mmol), and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.94 ml, 33.1 mmol) in DMF (50mL) was added methylamine, 2M in THF (16.6 mL, 33.1 mmol). The mixturewas stirred overnight at room temperature. Water (100 mL) was added tothe mixture and stirred. The resultant precipitate was collected byfiltration and dried to give 5.15 g of6-bromo-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine as pale yellow solid(99%) LCMS m/z=315 (M+1) (Method D) (retention time=1.34 min). ¹H NMR(300 MHz, DMSO) δ 9.60 (dd, J=2.1, 0.8 Hz, 1H), 8.79-8.70 (m, 1H), 8.67(dd, J=4.8, 1.7 Hz, 1H), 8.57 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 7.90 (dd,J=8.9, 2.1 Hz, 1H), 7.71 (d, J=8.9 Hz, 1H) 7.52 (ddd, J=7.9, 4.8, 0.9Hz, 1H), 3.13 (d, J=4.5 Hz, 3H).

Method AQ2:6-(6-methoxypyridin-3-yl)-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine(Iviii-f)

To a 1 dram reaction vial was added6-bromo-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine (35 mg, 0.111mmol), 6-methoxypyridin-3-ylboronic acid (20.4 mg, 0.133 mmol),Pd(APhos)₂Cl₂ (3.2 mg, 0.0041 mmol) and potassium phosphate monohydrate(77 mg, 0.33 mmol) in a mixture of dioxane-water (9:1, 2 mL). Thereaction mixture was heated to 90° C. for 14 h after which it was cooledto room temperature and diluted with water (5 mL). The resultantprecipitate was collected by filtration and recrystallized from methanolto give6-(6-methoxypyridin-3-yl)-N-methyl-2-(pyridine-3-yl)quinazoline-4-amineas a pale yellow solid (19.1 mg, 51%). LCMS m/z=344 (M+1) (Method C)(retention time=2.01 min) ¹H NMR (300 MHz, DMSO) δ 9.64 (d, J=1.3 Hz,1H), 8.84-8.74 (m, 1H), 8.68 (dd, J=6.2, 1.7 Hz, 2H), 8.57 (d, J=1.6 Hz,2H), 8.16 (ddd, J=14.4, 8.7, 2.2 Hz, 2H), 7.85 (d, J=8.7 Hz, 1H), 7.54(dd, J=7.9, 4.8 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 3.93 (s, 3H), 3.18 (d,J=4.3 Hz, 3H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 72 or 74, replacing methylamine with theappropriate amine and 6-methoxypyridin-3-ylboronic acid with theappropriate boronic acid.

TABLE 24 Method Molec- Reten- for ular ¹H-NMR tion LCMS Purity Cou-Number Product Salt Mass ¹H-NMR Solvent LCMS Time Protocol percent pling1248

HCl 342.4 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.66 (s, 1H), 8.50-8.89 (m, 3H),8.16 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.30-7.61 (m, 4H),7.01 (d, J = 6.4 Hz, 1H), 3.88 (s, 3H), 3.32 (brs, 1H), 3.19 (s, 3H).DMSO 343.1 (M + 1) Method B (NH4HCO3) 95 Method AQ1 1249

372.4 1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.77 (d, J = 7.9 Hz,1H), 8.67 (d, J = 3.7 Hz, 1H), 8.50 (s, 1H), 8.11 (s, 1H), 7.56-7.53 (m,2H), 7.48-7.40 (m, 3H), 7.01 (d, J = 3.9 Hz, 1H), 4.07 (s, 3H), 3.88 (s,3H), 3.17 (d, J = 4.0 Hz, 3H). DMSO 372.9 (M + 1) Method B (NH4HCO3) 95Method AQ1 1250

356.4 1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.79-8.74 (m, 1H), 8.69(d, J = 4.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H),7.57-7.51 (m, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.37- 7.30 (m, 1H),7.02-6.92 (m, 3H), 3.82 (s, 3H), 3.18 (d, J = 4.0 Hz, 3H), 2.69 (s, 3H).DMSO 357.1 (M + 1) Method B (NH4HCO3) 95 Method AQ1 1251

356.4 1H-NMR (400 MHz, DMSO-d6): δ 9.68 (d, J = 1.2 Hz, 1H), 8.75 (d, J= 8.0 Hz, 1H), 8.62 (d, J = 4.6 Hz, 1H), 8.49 (d, J = 4.4 Hz, 1H), 8.35(s, 1H), 7.97 (s, 1H), 7.49 (dd, J = 7.8, 4.8 Hz, 1H), 7.44-7.29 (m,3H), 6.93 (dd, J = 6.8, 2.4 Hz, 1H), 3.81 (s, 3H), 3.12 (d, J = 4.4 Hz,3H), 2.68 (s, 3H). DMSO 357.2 (M + 1) Method B (NH4HCO3) 95 Method AQ11252

329.3 1H NMR (300 MHz, DMSO) δ 9.31 (s, 1H), 8.76 (d, J = 4.7 Hz, 1H),8.51 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.18 (dd, J = 8.5,2.2 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 7.9, 4.8 Hz, 1H),7.49-7.23 (m, 3H), 6.99 (d, J = 6.7 Hz, 1H), 3.85 (s, 3H). DMSO 330(M + 1) 1.76 Method D 100 1253

HCl 342.4 1H NMR (300 MHz, DMSO) δ 10.11 (s, 1H), 9.63 (s, 1H), 9.07-8.86 (m, 2H), 8.58 (s, 1H), 8.16 (s, 2H), 7.92-7.77 (m, 1H), 7.54- 7.36(m, 2H), 7.20 (d, J = 8.6 Hz, 1H), 7.16-7.07 (m, 1H), 3.81 (s, 3H), 3.29(d, J = 3.9 Hz, 3H). DMSO 343 (M + 1) 1.47 Method D 100 Method AQ2 1254

330.3 1H NMR (300 MHz, DMSO) δ 9.59 (s, 1H), 8.73 (d, J = 8.3 Hz, 1H),8.65 (d, J = 4.7 Hz, 1H), 8.37-8.22 (m, 1H), 8.18-8.05 (m, 1H), 7.76 (d,J = 9.0 Hz, 1H), 7.71 (s, 1H), 7.56-7.43 (m, 2H), 4.58 (s, 2H), 3.14 (d,J = 4.4 Hz, 3H), 2.69 (d, J = 4.6 Hz, 3H). DMSO 331 (M + 1) 1.52 MethodD 100 Method AQ2 1255

312.4 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.88-8.47 (m, 4H),8.25-8.05 (m, 1H), 7.97-7.72 (m, 3H), 7.67-7.35 (m, 4H), 3.18 (d, J =4.4 Hz, 3H). DMSO 313 (M + 1) 1.48 Method D 100 Method AQ2 1256

HCl 337.4 1H NMR (300 MHz, DMSO) δ 9.93 (s, 1H), 9.63 (s, 1H), 9.00 (d,J = 8.3 Hz, 1H), 8.95-8.82 (m, 2H), 8.46-8.32 (m, 2H), 8.25 (d, J = 7.0Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.88-7.70(m, 2H), 3.29 (d, J = 4.2 Hz, 3H). DMSO 338 (M + 1) 1.50 Method D 100Method AQ2 1257

337.4 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.77 (d, J = 7.9 Hz, 1H),8.73-8.59 (m, 3H), 8.21 (d, J = 8.8 Hz, 1H), 8.11-7.94 (m, 4H), 7.87 (d,J = 8.7 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 3.18 (d, J = 4.0 Hz,3H). DMSO 338 (M + 1) 1.50 Method D 100 Method AQ2 1258

346.8 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.77 (d, J = 7.9 Hz, 1H),8.72-8.52 (m, 3H), 8.14 (d, J = 8.7 Hz, 1H), 7.97- 7.74 (m, 3H),7.68-7.45 (m, 3H), 3.18 (d, J = 4.0 Hz, 3H). DMSO 347 (M + 1) 1.60Method D 100 Method AQ2 1259

346.8 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.78 (d, J = 8.0 Hz, 1H),8.72-8.54 (m, 3H), 8.17 (d, J = 8.7 Hz, 1H), 7.94 (s, 1H), 7.90-7.78 (m,2H), 7.61- 7.42 (m, 3H), 3.19 (d, J = 4.4 Hz, 3H). DMSO 347 (M + 1) 1.66Method D 100 Method AQ2 1260

372.4 1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 8.77 (dd, J = 7.9, 1.8 Hz,1H), 8.67 (d, J = 4.7 Hz, 1H), 8.46 (d, J = 4.4 Hz, 1H), 8.26 (s, 1H),7.95-7.84 (m, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.53 (dd, J = 7.9, 4.8 Hz,1H), 7.35 (d, J = 8.3 Hz, 1H), 6.77- 6.60 (m, 2H), 3.80 (ss, 6H), 3.14(d, J = 4.3 Hz, 3H). DMSO 373 (M + 1) 1.49 Method D 100 Method AQ2 1261

348.3 1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 8.77 (dd, J = 8.0, 1.9 Hz,1H), 8.68 (d, J = 4.6 Hz, 1H), 8.59 (s, 2H), 8.21-8.09 (m, 1H),8.02-7.88 (m, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.71 (s, 1H), 7.67- 7.58(m, 1H), 7.53 (dd, J = 7.6, 5.1 Hz, 1H), 3.18 (d, J = 4.4 Hz, 3H). DMSO349 (M + 1) 1.61 Method D 100 Method AQ2 1262

313.4 1H NMR (300 MHz, DMSO) δ 9.65 (s, 1H), 9.09 (s, 1H), 8.78 (d, J =8.0 Hz, 1H), 8.73-8.55 (m, 4H), 8.30-8.14 (m, 2H), 7.89 (d, J = 8.6 Hz,1H), 7.63-7.47 (m, 2H), 3.19 (d, J = 4.3 Hz, 3H). DMSO 314 (M + 1) 1.70Method C 96 Method AQ2 1263

343.4 1H NMR (300 MHz, DMSO) δ 9.64 (d, J = 1.3 Hz, 1H), 8.84- 8.74 (m,1H), 8.68 (dd, J = 6.2, 1.7 Hz, 2H), 8.57 (d, J = 1.6 Hz, 2H), 8.16(ddd, J = 14.4, 8.7, 2.2 Hz, 2H), 7.85 (d, J = 8.7 Hz, 1H), 7.54 (dd, J= 7.9, 4.8 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 3.93 (s, 3H), 3.18 (d, J =4.3 Hz, 3H). DMSO 344.1 (M + 1) 1.94 Method C 95 Method AQ2 1264

356.4 1H NMR (300 MHz, DMSO) δ 10.76 (s, 1H), 9.75 (d, J = 1.6 Hz, 1H),9.23 (d, J = 8.2 Hz, 1H), 9.05-8.86 (m, 2H), 8.41-8.24 (m, 2H),8.24-8.05 (m, 2H), 7.96 (dd, J = 8.1, 5.2 Hz, 1H), 6.56 (d, J = 9.5 Hz,1H), 4.81 (s, 2H), 3.34 (s, 3H), 3.29 (d, J = 4.3 Hz, 3H). DMSO 357.1(M + 1) 2.13 Method C 100 Method AQ2 1265

342.4 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.78 (dd, J = 8.0, 1.9 Hz,1H), 8.67 (dd, J = 6.3, 4.7 Hz, 2H), 8.58 (s, 1H), 8.17- 8.06 (m, 1H),7.86 (d, J = 8.7 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H),7.60-7.44 (m, 2H), 7.37 (d, J = 7.5 Hz, 1H), 5.31 (t, J = 5.4 Hz, 1H),4.62 (d, J = 4.9 Hz, 2H), 3.18 (d, J = 4.4 Hz, 3H). DMSO 343.1 (M + 1)1.78 Method C 99 Method AQ2 1266

344.4 1H NMR (300 MHz, DMSO) δ 9.65 (d, J = 2.1 Hz, 1H), 8.92- 8.59 (m,3H), 8.59-8.47 (m, 1H), 8.40-8.11 (m, 2H), 8.04 (d, J = 8.5 Hz, 1H),7.58 (dd, J = 7.9, 4.8 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 4.29 (s, 3H),3.93 (s, 3H). DMSO 345.1 (M + 1) 2.32 Method C 100 Method AQ2 1267

329.4 1H NMR (300 MHz, DMSO) δ 12.77 (s, 1H), 9.33 (d, J = 1.7 Hz, 1H),8.77 (dd, J = 4.7, 1.5 Hz, 1H), 8.60-8.46 (m, 1H), 8.23 (d, J = 8.3 Hz,1H), 8.04 (d, J = 1.5 Hz, 1H), 7.87 (dd, J = 8.3, 1.8 Hz, 1H), 7.67-7.53(m, 1H), 7.52-7.29 (m, 3H), 7.04 (ddd, J = 7.7, 2.4, 1.5 Hz, 1H), 3.57(s, 3H). DMSO 330 (M + 1) 1.78 Method C 100 Method AQ2 1268

342.4 1H NMR (300 MHz, DMSO) δ 9.65 (dd, J = 2.1, 0.8 Hz, 1H), 8.84-8.74(m, 1H), 8.68 (dd, J = 4.7, 1.7 Hz, 1H), 8.52 (d, J = 4.4 Hz, 1H), 8.30(d, J = 8.6 Hz, 1H), 8.03 (d, J = 1.7 Hz, 1H), 7.85 (dd, J = 8.5, 1.8Hz, 1H), 7.54 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.47-7.34 (m, 3H),7.08-6.96 (m, 1H), 3.34 (s, 3H), 3.17 (d, J = 4.4 Hz, 3H). DMSO 343.3(M + 1) 2.09 Method C Method AQ2 1269

342.4 1H NMR (300 MHz, DMSO) δ 9.53 (d, J = 2.0 Hz, 1H), 8.65 (dd, J =5.9, 3.5 Hz, 2H), 8.51 (d, J = 4.2 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H),7.84 (d, J = 7.3 Hz, 1H), 7.65-7.25 (m, 5H), 7.00 (dd, J = 8.1, 2.6 Hz,1H), 3.33 (s, 3H), 3.17 (d, J = 4.2 Hz, 3H). DMSO 343.3 (M + 1) 2.16Method C 100 Method AQ2 1270

2HCl 374.5 1H NMR (300 MHz, DMSO) δ 10.67 (s, 1H), 9.69 (s, 1H), 9.12(d, J = 11.6 Hz, 2H), 8.97 (d, J = 5.0 Hz, 1H), 8.43 (d, J = 7.4 Hz,1H), 8.31 (d, J = 8.6 Hz, 1H), 8.20 (s, 1H), 8.07 (s, 1H) 7.98-7.86 (m,1H), 7.77 (s, 2H), 3.31 (d, J = 3.9 Hz, 3H), 2.90 (s, 3H). DMSO 375.1(M + 1) 1.67 Method C 95 Method AQ2 1271

374.5 1H NMR (300 MHz, DMSO) δ 9.70-9.57 (m, 1H), 8.84-8.72 (m, 1H),8.73-8.62 (m, 3H), 8.19 (dd, J = 8.7, 1.9 Hz, 1H), 8.06 (d, J = 8.4 Hz,2H), 7.86 (dd, J = 10.6, 8.5 Hz, 3H), 7.60-7.49 (m, 1H), 3.19 (d, J =4.4 Hz, 2H), 2.81 (s, 3H). DMSO 375.1 (M + 1) 1.64 Method C 95 MethodAQ2 1272

2HCl 425.5 1H NMR (300 MHz, DMSO) δ 10.54 (s, 1H), 9.70 (d, J = 1.7 Hz,1H), 9.12 (d, J = 8.1 Hz, 1H), 8.98 (dd, J = 5.5, 4.0 Hz, 2H), 8.37 (dd,J = 26.8, 7.9 Hz, 2H), 8.09-7.84 (m, 3H), 7.63 (t, J = 7.7 Hz, 1H), 7.49(d, J = 7.6 Hz, 1H), 3.67 (bs, 8H), 3.31 (d, J = 4.3 Hz, 3H). DMSO 426.2(M + 1) 1.72 Method C 95 Method AQ2 1273

HCl 342.4 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.77 (d, J = 7.9 Hz,1H), 8.71-8.65 (m, 1H), 8.60 (s, 1H), 8.53 (s, 1H), 8.10 (d, J = 8.7 Hz,1H), 7.87-7.77 (m, 3H), 7.59-7.49 (m, 1H), 7.10 (d, J = 8.7 Hz, 2H),3.83 (d, J = 0.9 Hz, 3H), 3.19 (s, 3H). DMSO 343.1 (M + 1) 2.06 Method C100 Method AQ2 1274

329.4 1H NMR (300 MHz, DMSO) δ 9.34 (d, J = 1.5 Hz, 1H), 8.74 (dd, J =4.8, 1.6 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H),8.10 (dd, J = 8.5, 2.3 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.76 (s, 1H),7.73 (s, 1H), 7.58 (dd, J = 8.0, 4.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H),3.82 (s, 3H). DMSO 330.0 (M + 1) 1.75 Method C 100 Method AQ2 1275

343.4 1H NMR (300 MHz, DMSO) δ 9.65 (d, J = 1.5 Hz, 1H), 8.84- 8.65 (m,4H), 8.31 (d, J = 5.4 Hz, 1H), 8.24 (dd, J = 8.7, 1.9 Hz, 1H), 7.87 (d,J = 8.7 Hz, 1H), 7.59-7.46 (m, 2H), 7.33 (d, J = 0.9 Hz, 1H), 3.93 (s,3H), 3.20 (d, J = 4.4 Hz, 3H). DMSO 344.1 (M + 1) 1.95 Method C 95Method AQ2 1276

331.3 1H NMR (300 MHz, DMSO) δ 9.63 (d, J = 1.4 Hz, 1H), 8.81- 8.74 (m,1H), 8.73 (d, J = 2.3 Hz, 1H), 8.68 (dd, J = 4.7, 1.7 Hz, 1H), 8.66-8.56(m, 2H), 8.44 (td, J = 8.2, 2.6 Hz, 1H), 8.18 (dd, J = 8.7, 2.0 Hz, 1H),7.87 (d, J = 8.7 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 7.38 (dd, J =8.5, 2.9 Hz, 1H), 3.18 (d, J = 4.4 Hz, 3H). DMSO 332.1 (M + 1) 1.89Method C 100 Method AQ2 1277

425.5 1H NMR (300 MHz, DMSO) δ 9.63 (d, J = 1.4 Hz, 1H), 8.77 (d, J =8.0 Hz, 1H), 8.70-8.59 (m, 3H), 8.15 (dd, J = 8.7, 1.6 Hz, 1H), 7.92 (d,J = 8.2 Hz, 2H), 7.85 (d, J = 8.7 Hz, 1H), 7.62- 7.48 (m, 3H), 3.62 (s,J = 54.7 Hz, 8H), 3.17 (d, J = 4.2 Hz, 3H). DMSO 426.2 (M + 1) 1.69Method C 100 Method AQ2 1278

343.4 1H NMR (300 MHz, DMSO) δ 9.67 (d, J = 1.5 Hz, 1H), 8.86- 8.77 (m,1H), 8.74 (dd, J = 4.7, 1.6 Hz, 1H), 8.37-8.25 (m, 2H), 8.06 (d, J = 8.7Hz, 1H), 7.60 (dd, J = 7.9, 4.1 Hz, 1H), 7.50- 7.30 (m, 3H), 7.02 (dd, J= 7.9, 1.4 Hz, 1H), 4.31 (s, 3H), 3.87 (s, 3H). DMSO 344.2 (M + 1) 2.47Method C 100 Method AQ2 Starting Starting Number Material 1 Material 2Product 1279

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Salt ¹H NMR Purity Method of LCMS Number type ¹H NMR Solvent percentCoupling LCMS Method 1279 2 HCl ¹H NMR (400 MHz, DMSO) δ 9.69 (d, J =1.8 Hz, 1H), 9.40-9.33 (m, 1H), 9.03-8.93 (m, 2H), 8.64-8.59 (m, 1H),8.18-8.14 (m, 1H), 8.13-8.05 (m, 3H), 8.04-7.97 (m, 2H), 3.21 (d, J =4.4 Hz, 3H), 2.77 (s, 3H). DMSO >98 AQ3 1280 2 HCl ¹H NMR (400 MHz,DMSO) δ 9.71- 9.65 (m, 1H), 9.44-9.36 (m, 1H), 9.06-8.94 (m, 2H), 8.59-8.54 (m, 1H), 8.19-8.10 (m, 2H), 7.79-7.71 (m, 2H), 7.61- 7.54 (m, 1H),7.29-7.22 (m, 1H), 3.21 (d, J = 3.9 Hz, 3H), 2.76 (s, 3H). DMSO >98 AQ31281 2 HCl ¹H NMR (400 MHz, DMSO) δ 9.72- 9.65 (m, 1H), 9.43-9.36 (m,1H), 9.04-8.91 (m, 2H), 8.63- 8.55 (m, 1H), 8.36-8.31 (m, 1H), 8.26-8.20(m, 1H), 8.20- 8.11 (m, 2H), 7.91-7.85 (m, 1H), 7.78-7.70 (m, 1H), 3.22(d, J = 4.2 Hz, 3H), 2.76 (s, 3H). DMSO >98 AQ3 1282 2 HCl ¹H NMR (400MHz, DMSO) δ 9.70- 9.65 (m, 1H), 9.37 (d, J = 8.2 Hz, 1H), 9.03-8.90 (m,2H), 8.49-8.42 (m, 1H), 8.12 (dd, J = 8.1, 5.6 Hz, 1H), 8.08-8.03 (m,1H), 7.88-7.78 (m, 2H), 7.15- 7.04 (m, 2H), 3.84 (s, 3H), 3.21 (d, J =3.9 Hz, 3H), 2.76 (s, 3H). DMSO >98 AQ3 1283 2 HCl ¹H NMR (400 MHz,DMSO) δ 9.73- 9.67 (m, 1H), 9.36 (d, J = 7.4 Hz, 1H), 9.02-8.96 (m, 1H),8.82 (s, 1H), 8.26-8.19 (m, 1H), 8.15-8.07 (m, 1H), 7.89-7.83 (m, 1H),7.47-7.38 (m, 2H), 7.21-7.15 (m, 1H), 7.14-7.06 (m, 1H), 3.81 (s, 3H),3.19 (d, J = 4.5 Hz, 3H), 2.77 (s, 3H). DMSO >98 AQ3 1284 2 HCl ¹H NMR(400 MHz, DMSO) δ 9.72 (d, J = 1.8 Hz, 1H), 9.34-9.28 (m, 1H), 8.95 (dd,J = 5.4, 1.4 Hz, 1H), 8.88-8.78 (m, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.07-8.00 (m, 2H), 7.95-7.90 (m, 1H), 7.90-7.83 (m, 1H), 7.76 (dd, J = 7.8,0.7 Hz, 1H), 7.68- 7.63 (m, 1H), 3.19 (d, J = 4.5 Hz, 3H), 2.77 (s, 3H).DMSO >98 AQ3 1285 ¹H NMR (400 MHz, DMSO) δ 9.63 (dd, J = 2.1, 0.8 Hz,1H), 8.80- 8.75 (m, 1H), 8.69 (dd, J = 3.7, 1.8 Hz, 1H), 7.72 (d, J =8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.58-7.49 (m, 2H), 7.46-7.40 (m,1H), 7.39-7.32 (m, 1H), 7.28-7.18 (m, 1H), 3.18 (d, J = 4.4 Hz, 3H),2.64 (s, 3H). DMSO >98 AQ4 1286 2 HCl ¹H NMR (400 MHz, DMSO) δ 9.67-9.60 (m, 1H), 9.06-8.88 (m, 3H), 8.12 (d, J = 8.8 Hz, 1H), 7.91-7.79 (m,2H), 7.53-7.40 (m, 2H), 7.34-7.24 (m, 1H), 3.34 (d, J = 4.6 Hz, 3H),2.66 (s, 3H). DMSO >98 AQ4 1287 HCl ¹H NMR (400 MHz, DMSO) δ 9.62- 9.57(m, 1H), 8.94-8.86 (m, 2H), 8.62 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H),7.86-7.75 (m, 2H), 7.52-7.36 (m, 2H), 7.35-7.28 (m, 1H), 3.31 (d, J =4.5 Hz, 3H), 2.67 (s, 3H). DMSO >98 AQ4 1288 HCl ¹H NMR (400 MHz, DMSO)δ 9.63- 9.58 (m, 1H), 8.95-8.86 (m, 2H), 8.73 (s, 1H), 8.01 (d, J = 8.5Hz, 1H), 7.87-7.75 (m, 2H), 7.61-7.50 (m, 1H), 7.45-7.33 (m, 3H), 3.32(d, J = 4.5 Hz, 3H), 2.66 (s, 3H). DMSO >98 AQ4 1289 2 HCl ¹H NMR (400MHz, DMSO) δ 9.64- 9.60 (m, 1H), 9.00-8.86 (m, 3H), 8.06 (d, J = 8.5 Hz,1H), 7.91-7.79 (m, 2H), 7.65-7.55 (m, 1H), 7.37-7.29 (m, 1H), 7.29-7.22(m, 2H), 3.35 (d, J = 4.6 Hz, 3H), 2.72 (s, 3H). DMSO >98 AQ4 1290 2 HCl¹H NMR (400 MHz, DMSO) δ 9.69- 9.64 (m, 1H), 9.14-8.99 (m, 2H), 8.96(dd, J = 5.0, 1.5 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.90-7.81 (m, 2H),7.50-7.34 (m, 4H), 3.35 (d, J = 4.6 Hz, 3H), 2.72 (s, 3H). DMSO >98 AQ41291 HCl ¹H NMR (300 MHz, CDCl₃) δ 9.63 (s, 2H), 8.96 (d, J = 8.2 Hz,1H), 8.90 (d, J = 5.0 Hz, 1H), 8.50 (s, 1H), 8.16-7.99 (m, 2H), 7.82(dd, J = 8.0, 4.9 Hz, 1H), 7.71- 7.62 (m, 1H), 7.61-7.47 (m, 3H), 3.26(d, J = 4.5 Hz, 3H). DMSO >98 G2/AQ3 1292 2 HCl ¹H NMR (300 MHz, CDCl₃)δ 10.27 (s, 1H), 9.69 (s, 1H), 9.09 (d, J = 8.1 Hz, 1H), 8.97 (d, J =5.0 Hz, 1H), 8.56 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.7Hz, 1H), 7.89 (dd, J = 8.0, 5.1 Hz, 1H), 7.45-7.26 (m, 4H), 3.29 (d, J =4.2 Hz, 3H), 2.32 (s, 3H). DMSO >98 G2/AQ3 1293 2 HCl ¹H NMR (300 MHz,DMSO) δ 10.40 (s, 1H), 9.73 (s, 1H), 9.15 (d, J = 7.9 Hz, 1H), 8.98 (d,J = 5.1 Hz, 1H), 8.67 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 8.18 (d, J =8.7 Hz, 1H), 7.91 (dd, J = 7.9, 5.2 Hz, 1H), 7.45 (m, 2H), 7.20 (d, J =8.2 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 3.82 (s, 3H), 3.29 (d, J = 4.1Hz, 3H). DMSO >98 G2/AQ3 1294 ¹H NMR (300 MHz, CDCl₃) δ 9.66 (s, 1H),8.80 (d, J = 7.9 Hz, 1H), 8.74-8.67 (m, 1H), 8.60 (m, 1H), 8.49 (s, 1H),8.00 (dd, J = 18.5, 10.4 Hz, 2H), 7.96-7.81 (m, 2H), 7.76 (d, J = 7.6Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.56 (dd, J = 7.6, 5.0 Hz, 1H), 3.18(d, J = 4.2 Hz, 3H). DMSO >98 G2/AQ3 1295 2 HCl ¹H NMR (300 MHz, CDCl₃)δ 9.88 (s, 1H), 9.66 (s, 1H), 9.01 (d, J = 8.3 Hz, 1H), 8.90 (d, J = 4.2Hz, 1H), 8.70 (s, 1H), 8.27-8.08 (m, 2H), 7.81 (dd, J = 8.0, 5.1 Hz,1H), 7.72 (t, J = 7.6 Hz, 1H), 7.60- 7.48 (m, 1H), 7.48-7.27 (m, 2H),3.27 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3 1296 2 HCl ¹H NMR (300 MHz,CDCl₃) δ 9.63 (m, 2H), 8.93 (d, J = 7.7 Hz, 1H), 8.88 (d, J = 4.1 Hz,1H), 8.76 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H),7.94 (dd, J = 8.6, 5.5 Hz, 2H), 7.82- 7.73 (m, 1H), 7.41 (t, J = 8.7 Hz,2H), 3.28 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3 1297 2 HCl ¹H NMR (300MHz, DMSO) δ 9.82 (s, 1H), 9.64 (d, J = 1.7 Hz, 1H), 9.00 (d, J = 8.0Hz, 1H), 8.95- 8.86 (m, 2H), 8.69 (t, J = 1.9 Hz, 1H), 8.51-8.34 (m,2H), 8.30 (dd, J = 7.9, 1.8 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.93-7.76(m, 2H), 3.30 (d, J = 4.5 Hz, 3H). DMSO >98 G2/AQ3 1298 2 HCl ¹H NMR(300 MHz, DMSO) δ 10.30 (s, 1H), 9.70 (d, J = 2.1 Hz, 1H), 9.11 (d, J =8.2 Hz, 1H), 9.04-8.83 (m, 1H), 8.56 (s, 1H), 8.26 (d, J = 8.6 Hz, 1H),8.01- 7.80 (m, 3H), 7.78-7.64 (m, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.54(d, J = 7.2 Hz, 1H), 3.29 (d, J = 4.4 Hz, 3H), 2.44 (s, 3H). DMSO >98G2/AQ3 1299 ¹H NMR (300 MHz, DMSO) δ 10.50 (s, 1H), 9.66 (s, 1H), 9.09(d, J = 8.2 Hz, 1H), 9.01 (s, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.40 (d, J= 8.7 Hz, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.13-8.00 (m, 4H), 7.88 (dd, J= 8.0, 5.2 Hz, 1H), 3.30 (d, J = 4.1 Hz, 3H), 2.62 (s, 3H). DMSO >98G2/AQ3 1300 2 HCl ¹H NMR (300 MHz, DMSO) δ 10.49 (s, 1H), 9.66 (s, 1H),9.09 (d, J = 7.9 Hz, 1H), 9.01 (s, 1H), 8.95 (d, J = 5.0 Hz, 1H), 8.40(d, J = 8.6 Hz, 1H), 8.29 (d, J = 8.7 Hz, 1H), 8.15-7.94 (m, 4H), 7.88(dd, J = 7.9, 5.2 Hz, 1H), 3.31 (d, J = 4.1 Hz, 3H), 2.63 (s, 3H).DMSO >98 G2/AQ3 1301 2 HCl ¹H NMR (300 MHz, DMSO) δ 10.97 (s, 1H), 9.71(d, J = 2.0 Hz, 1H), 9.29 (s, 1H), 9.15 (d, J = 8.0 Hz, 1H), 8.98 (dd, J= 5.0, 1.3 Hz, 1H), 8.49-8.38 (m, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.21(s, 1H), 7.92 (dd, J = 8.1, 5.1 Hz, 1H), 7.84 (s, 1H), 7.69-7.52 (m,2H), 3.31 (d, J = 4.3 Hz, 3H), 3.23 (s, 6H). DMSO >98 G2/AQ3 1302 2 HCl¹H NMR (300 MHz, DMSO) δ 10.33 (s, 1H), 9.73 (d, J = 1.7 Hz, 1H), 9.20(d, J = 8.0 Hz, 1H), 9.00 (d, J = 4.2 Hz, 1H), 8.68 (s, 1H), 8.32 (d, J= 8.6 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.01- 7.93 (m, 2H), 7.90 (t, J= 7.2 Hz, 1H), 7.74 (dd, J = 15.4, 7.7 Hz, 2H), 3.24 (t, J = 18.2 Hz,3H). DMSO >98 G2/AQ3 1303 HCl ¹H NMR (300 MHz, DMSO) δ 10.46 (s, 1H),9.76 (d, J = 2.1 Hz, 1H), 9.21 (d, J = 8.2 Hz, 1H), 9.00 (dd, J = 5.1,1.2 Hz, 1H), 8.58 (d, J = 1.3 Hz, 1H), 8.41 (d, J = 8.6 Hz, 1H),8.08-7.86 (m, 2H), 7.36-7.09 (m, 3H), 3.29 (d, J = 4.3 Hz, 3H), 2.33 (s,3H), 2.17 (s, 3H). DMSO >98 G2/AQ3 1304 ¹H NMR (300 MHz, DMSO) δ 9.65(d, J = 2.1 Hz, 1H), 8.79 (dt, J = 8.0, 1.9 Hz, 1H), 8.69 (dd, J = 4.7,1.6 Hz, 1H), 8.46 (d, J = 4.5 Hz, 1H), 8.20 (d, J = 1.7 Hz, 1H), 7.83(d, J = 8.5 Hz, 1H), 7.75 (dd, J = 8.5, 1.6 Hz, 1H), 7.54 (dd, J = 7.9,4.8 Hz, 1H), 7.28- 7.02 (m, 3H), 3.33 (s, 6H), 3.15 (d, J = 4.4 Hz, 3H),2.51 (dt, J = 3.6, 1.7 Hz, 1H), 2.35 (s, 3H), 2.27 (s, 3H). DMSO >98G2/AQ3 1305 HCl ¹H NMR (300 MHz, DMSO) δ 10.48 (s, 1H), 9.70 (s, 1H),9.11 (d, J = 7.8 Hz, 1H), 8.97 (d, J = 4.7 Hz, 1H), 8.90 (s, 1H), 8.36(d, J = 8.6 Hz, 1H), 8.29 (d, J = 8.7 Hz, 1H), 7.98-7.80 (m, 1H), 7.74(s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 3.32 (d, J= 4.0 Hz, 3H), 2.33 (d, J = 10.0 Hz, 3H), 2.29 (s, 3H). DMSO >98 G2/AQ31306 HCl ¹H NMR (300 MHz, DMSO) δ 10.45-10.35 (m, 1H), 9.69 (s, 1H),9.09 (s, 1H), 8.99 (s, 1H), 8.88 (s, 1H), 8.37 (d, J = 8.6 Hz 1H), 8.28(d, J = 8.7 Hz, 1H), 7.94 (s, 1H), 7.54 (s, 1H), 7.11 (s, 1H), 3.34 (d,J = 4.3 Hz, 3H), 2.40 (s, 3H). DMSO >98 G2/AQ3 1307 2 HCl ¹H NMR (300MHz, DMSO) δ 10.28 (s, 1H), 9.84-9.66 (m, 1H), 9.17 (d, J = 8.1 Hz, 1H),8.99 (d, J = 5.0 Hz, 1H), 8.46 (s, 1H), 8.36 (d, J = 8.6 Hz, 1H),7.98-7.80 (m, 2H), 7.41 (t, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H),3.71 (s, 6H), 3.29 (d, J = 4.2 Hz, 3H). DMSO >98 G2/AQ3 1308 HCl ¹H NMR(300 MHz, DMSO) δ 9.64 (s, 1H), 8.96-8.91 (m, 1H), 8.89- 8.83 (m, 2H),8.41 (d, J = 9.1 Hz, 2H), 8.38-8.32 (m, 1H), 8.16 (d, J = 9.0 Hz, 2H),8.02 (d, J = 9.1 Hz, 1H), 7.81-7.73 (m, 1H), 3.27 (d, J = 4.3 Hz, 3H).DMSO >98 G2/AQ3 1309 ¹H NMR (300 MHz, DMSO) δ 9.64 (d, J = 2.0 Hz, 1H),8.78 (ddd, J = 14.6, 8.2, 6.5 Hz, 1H), 8.70 (dd, J = 4.7, 1.4 Hz, 1H),8.56 (d, J = 4.3 Hz, 1H), 8.33 (d, J = 1.5 Hz, 1H), 8.06 (dd, J = 8.6,1.4 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.56 (dd, J = 7.9, 4.8 Hz, 1H),7.34 (t, J = 7.5 Hz, 2H), 7.20- 7.00 (m, 2H), 3.16 (d, J = 4.4 Hz, 3H).DMSO >98 G2/AQ3 1310 2 HCl ¹H NMR (300 MHz, DMSO) δ 10.63 (s, 1H), 9.69(s, 1H), 9.16 (s, 1H), 9.10 (d, J = 7.9 Hz, 1H), 8.97 (d, J = 5.0 Hz,1H), 8.52 (s, 1H), 8.45 (d, J = 8.7 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H),8.07 (d, J = 7.8 Hz, 1H), 8.01-7.84 (m, 2H), 7.63 (t, J = 7.8 Hz, 1H),7.54 (s, 1H), 3.31 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3 1311 HCl ¹H NMR(300 MHz, DMSO) δ 10.20 (s, 1H), 9.65 (s, 1H), 9.02 (s, 1H), 8.95 (s,2H), 8.43 (d, J = 8.7 Hz, 1H), 8.26-8.14 (m, 1H), 8.04 (dd, J = 18.8,8.1 Hz, 4H), 7.88 (s, 1H), 7.47 (s, 1H), 3.32 (s, 3H), 3.17 (d, J = 1.8Hz, 9H). DMSO >98 G2/AQ3 1312 HCl ¹H NMR (300 MHz, DMSO) δ 9.79 (s, 1H),9.66 (d, J = 1.7 Hz, 1H), 9.02 (d, J = 8.1 Hz, 1H), 8.96- 8.86 (m, 1H),8.57 (s, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.05 (dd, J = 8.7, 1.4 Hz, 1H),7.82 (dd, J = 8.1, 5.0 Hz, 1H), 7.79-7.72 (m, 1H), 7.64-7.45 (m, 2H),3.25 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3 1313 2 HCl ¹H NMR (300 MHz,DMSO) δ 10.01 (s, 1H), 9.65 (s, 1H), 9.06 (d, J = 7.8 Hz, 1H), 8.95 (d,J = 4.8 Hz, 1H), 8.59 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 8.07 (d, J =9.1 Hz, 1H), 7.95-7.77 (m, 2H), 7.66-7.52 (m, 2H), 3.27 (d, J = 4.3 Hz,3H), 3.17 (d, J = 0.7 Hz, 1H). DMSO >98 G2/AQ3 1314 HCl ¹H NMR (300 MHz,DMSO) δ 10.10 (s, 1H), 9.69 (s, 1H), 9.13 (d, J = 8.0 Hz, 1H), 8.98 (d,J = 5.1 Hz, 1H), 8.62 (s, 1H), 8.27 (d, J = 8.6 Hz, 1H), 8.13 (d, J =8.3 Hz, 1H), 8.02-7.83 (m, 1H), 7.77-7.65 (m, 2H), 7.60 (d, J = 8.5 Hz,1H), 3.29 (d, J = 3.9 Hz, 3H). DMSO >98 G2/AQ3 1315 HCl ¹H NMR (300 MHz,DMSO) δ 9.62 (s, 1H), 9.02-8.93 (m, 1H), 8.89 (d, J = 4.5 Hz, 1H), 8.80(s, 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.18 (s, 1H), 8.04 (d, J = 8.7 Hz,1H), 7.96-7.75 (m, 2H), 3.29 (d, J = 4.2 Hz, 3H). DMSO >98 G2/AQ3 1316 2HCl ¹H NMR (300 MHz, DMSO) δ 10.36 (s, 1H), 9.67 (s, 1H), 9.13 (d, J =8.2 Hz, 1H), 9.01-8.82 (m, 2H), 8.40 (d, J = 9.1 Hz, 1H), 8.26 (d, J =8.7 Hz, 1H), 7.97 (s, 2H), 7.90 (dd, J = 8.0, 5.2 Hz, 1H), 7.65 (s, 1H),3.31 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3 1317 ¹H NMR (300 MHz, DMSO) δ9.65 (d, J = 1.9 Hz, 1H), 8.89-8.75 (m, 1H), 8.74-8.67 (m, 1H),8.67-8.56 (m, 1H), 8.48 (s, 1H), 8.06-7.94 (m, 1H), 7.87 (d, J = 8.7 Hz,1H), 7.68-7.51 (m, 2H), 7.46 (td, J = 9.6, 4.7 Hz, 1H), 7.39-7.21 (m,1H), 3.18 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3 1318 HCl ¹H NMR (300 MHz,DMSO) δ 10.57 (s, 1H), 9.69 (d, J = 2.0 Hz, 1H), 9.15 (d, J = 8.0 Hz,1H), 9.02 (s, 1H), 8.97 (d, J = 4.4 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H),8.29 (d, J = 8.7 Hz, 1H), 7.91 (dd, J = 8.0, 5.2 Hz, 1H), 7.77- 7.63 (m,2H), 7.37-7.18 (m, 1H), 3.29 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3 1319¹H NMR (300 MHz, CDCl₃) δ 9.58 (d, J = 2.0 Hz, 1H), 8.78-8.60 (m, 2H),8.35 (d, J = 1.7 Hz, 1H), 8.11-7.84 (m, 3H), 7.78 (d, J = 8.6 Hz, 1H),7.54 (dd, J = 7.9, 4.8 Hz, 1H), 7.48-7.34 (m, 2H), 7.17 (d, J = 8.1 Hz,1H), 7.10 (t, J = 7.4 Hz, 1H), 3.81 (s, 3H). DMSO >98 G2/AQ3 1320 ¹H NMR(300 MHz, CDCl₃) δ 9.62 (d, J = 2.1 Hz, 1H), 8.82-8.72 (m, 1H),8.72-8.66 (m, 1H), 8.30 (s, 1H), 7.93 (dd, J = 8.7, 1.2 Hz, 1H), 7.86(d, J = 8.6 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 7.50-7.33 (m, 2H),7.18 (d, J = 8.3 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 3.82 (s, 3H), 3.46(s, 6H). DMSO >98 G2/AQ3 1321 ¹H NMR (300 MHz, CDCl₃) δ 9.59 (d, J = 2.1Hz, 1H), 8.76-8.66 (m, 2H), 8.50 (s, 2H), 8.06 (brs, 1H), 7.99 (dt, J =8.6, 1.7 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.75-7.63 (m, 1H), 7.54 (dd,J = 7.9, 4.8 Hz, 1H), 7.52-7.44 (m, 1H), 7.44-7.32 (m, 2H). DMSO >98G2/AQ3 1322 ¹H NMR (300 MHz, CDCl₃) δ 9.59 (d, J = 2.1 Hz, 1H),8.79-8.62 (m, 3H), 8.21 (dd, J = 8.8, 1.9 Hz, 1H), 8.10 (brs, 2H), 7.86(d, J = 8.7 Hz, 1H), 7.80-7.69 (m, 2H), 7.68-7.49 (m, 2H), 7.32- 7.20(m, 1H). DMSO >98 G2/AQ3 1323 ¹H NMR (300 MHz, CDCl₃) δ 9.58 (d, J = 2.0Hz, 1H), 8.80-8.64 (m, 2H), 8.62 (d, J = 1.8 Hz, 1H), 8.14 (dd, J = 8.7,1.9 Hz, 1H), 8.07 (brs, 2H), 7.98-7.87 (m, 2H), 7.85 (d, J = 8.7 Hz,1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 7.38 (t, J = 8.8 Hz, 2H). DMSO >98G2/AQ3 1324 ¹H NMR (300 MHz, CDCl₃) δ 9.65- 9.57 (m, 1H), 8.82-8.70 (m,1H), 8.70-8.63 (m, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.11 (dd, J = 8.7, 1.7Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.72-7.60 (m, 2H), 7.60-7.47 (m, 2H),7.32-7.18 (m, 1H), 3.49 (s, 6H). DMSO >98 G2/AQ3 1325 ¹H NMR (400 MHz,DMSO) δ 9.64 (d, J = 1.4 Hz, 1H), 8.78 (dt, J = 8.3, 1.8 Hz, 1H), 8.69(dd, J = 4.7, 1.8 Hz, 1H), 8.61-8.46 (m, 2H), 8.40 (d, J = 1.6 Hz, 1H),7.99 (dd, J = 9.0, 1.8 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.54 (dd, J =8.4, 4.5 Hz, 1H), 3.99 (d, J = 8.9 Hz, 6H), 3.17 (d, J = 4.6 Hz, 3H).DMSO >98 G2/AQ3 1326 ¹H NMR (300 MHz, DMSO) δ 9.64- 9.55 (m, 1H),8.81-8.62 (m, 3H), 8.40 (s, 1H), 8.23 (dd, J = 8.8, 1.4 Hz, 1H), 8.13(d, J = 7.7 Hz, 1H), 8.00 (d, J = 7.7 Hz, 2H), 7.89 (d, J = 8.7 Hz, 1H),7.69 (t, J = 7.7 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 2.71 (s, 3H).DMSO >98 G2/AQ3 1327 ¹H NMR (300 MHz, DMSO) δ 9.58 (d, J = 2.1 Hz, 1H),8.76-8.65 (m, 3H), 8.24 (dd, J = 8.7, 1.8 Hz, 1H), 8.19-7.93 (m, 6H),7.88 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1HH), 2.65 (s, 3H).DMSO >98 G2/AQ3 1328 ¹H NMR (300 MHz, DMSO) δ 9.60 (d, J = 1.8 Hz, 1H),8.73 (dt, J = 8.0, 1.8 Hz, 1H), 8.69 (dd, J = 4.8, 1.6 Hz, 1H), 8.37 (s,1H), 7.99 (brs, 2H), 7.92-7.81 (m, 2H), 7.67-7.60 (m, 1H), 7.60- 7.52(m, 2H), 7.52-7.43 (m, 2H). DMSO >98 G2/AQ3 1329 ¹H NMR (300 MHz, DMSO)δ 9.60 (d, J = 2.0 Hz, 1H), 8.77-8.65 (m, 3H), 8.19 (dd, J = 8.7, 1.8Hz, 1H), 8.09 (brs, 2H), 7.99- 7.94 (m, 1H), 7.90-7.79 (m, 2H),7.63-7.51 (m, 2H), 7.48 (d, J = 8.1 Hz, 1H). DMSO >98 G2/AQ3 1330 ¹H NMR(300 MHz, DMSO) δ 9.65 (s, 1H), 8.87-8.75 (m, 1H), 8.70 (s, 1H), 8.55(s, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 8.09-7.76 (m, 3H), 7.62-7.44 (m,1H), 7.18 (s, 1H), 3.93 (s, 3H), 3.17 (s, 3H). DMSO >98 G2/AQ3 1331 ¹HNMR (300 MHz, DMSO) δ 9.61 (s, 1H), 8.75 (d, J = 7.6 Hz, 1H), 8.68 (s,1H), 8.45 (s, 1H), 8.18 (d, J = 9.2 Hz, 1H), 8.07 (d, J = 8.2 Hz, 2H),8.01-7.87 (m, 3H), 7.55 (s, 1H), 3.51 (s, 6H), 2.63 (s, 3H). DMSO >98G2/AQ3 1332 ¹H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 8.83-8.72 (m, 1H),8.70 (d, J = 3.3 Hz, 1H), 8.21 (s, 1H), 7.89 (q, J = 8.6 Hz, 2H), 7.74-7.41 (m, 5H), 3.47 (s, 6H). DMSO >98 G2/AQ3 1333 ¹H NMR (300 MHz, DMSO)δ 9.62 (d, J = 2.0 Hz, 1H), 8.76 (dt, J = 7.9, 1.8 Hz, 1H), 8.70 (dd, J= 4.8, 1.6 Hz, 1H), 8.38 (d, J = 1.9 Hz, 1H), 8.13 (dd, J = 8.7, 1.9 Hz,1H), 7.98-7.84 (m, 2H), 7.78 (d, J = 7.6 Hz, 1H), 7.66-7.41 (m, 3H),3.51 (s, 6H). DMSO >98 G2/AQ3 1334 2 HCl ¹H NMR (300 MHz, DMSO) δ 9.81-9.63 (m, 1H), 9.18 (d, J = 8.4 Hz, 1H), 9.07-8.89 (m, 1H), 8.39 (d, J =8.7 Hz, 1H), 8.31 (d, J = 1.7 Hz, 1H), 8.22-8.07 (m, 1H), 8.02 (dd, J =8.7, 1.7 Hz, 1H), 7.98-7.91 (m, 1H), 7.91- 7.83 (m, 1H), 7.80-7.68 (m,2H), 3.65 (s, 6H). DMSO >98 G2/AQ3 1335 ¹H NMR (300 MHz, DMSO) δ 9.65-9.62 (m, 1H), 8.82-8.75 (m, 1H), 8.73-8.68 (m, 1H), 8.61- 8.56 (m, 1H),8.50 (d, J = 2.0 Hz, 1H), 8.34-8.20 (m, 3H), 7.97 (d, J = 8.7 Hz, 1H),7.82 (t, J = 8.0 Hz, 1H), 7.57 (dd, J = 8.3, 5.2 Hz, 1H), 3.54 (s, 6H).DMSO >98 G2/AQ3 1336 ¹H NMR (300 MHz, DMSO) δ 9.61 (d, J = 1.8 Hz, 1H),8.80-8.72 (m, 1H), 8.72-8.67 (m, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.39-8.29 (m, 2H), 8.19 (dd, J = 8.7, 1.8 Hz, 1H), 8.14-8.07 (m, 2H), 7.94(d, J = 8.7 Hz, 1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H), 3.52 (s, 6H).DMSO >98 G2/AQ3 1337 2 HCl ¹H NMR (300 MHz, DMSO) δ 9.67- 9.61 (m, 1H),8.82-8.73 (m, 1H), 8.73-8.65 (m, 1H), 8.39 (s, 1H), 8.03-7.96 (m, 3H),7.90- 7.72 (m, 2H), 7.72-7.60 (m, 1H), 7.56 (dd, J = 7.6, 5.1 Hz, 1H),3.53 (s, 6H). DMSO >98 G2/AQ3 1338 ¹H NMR (300 MHz, DMSO) δ 9.65 (d, J =2.1 Hz, 1H), 8.78 (dt, J = 8.1, 1.8 Hz, 1H), 8.71-8.59 (m, 3H), 8.19(dd, J = 8.6, 1.7 Hz, 1H), 8.07-7.95 (m, 2H), 7.93- 7.81 (m, 2H), 7.54(dd, J = 7.9, 4.7 Hz, 1H), 7.47-7.34 (m, 2H), 3.23-3.20 (m, 3H).DMSO >98 G2/AQ3 1339 ¹H NMR (300 MHz, DMSO) δ 9.68- 9.64 (m, 1H),8.83-8.75 (m, 1H), 8.69 (d, J = 4.7 Hz, 1H), 8.56-8.45 (m, 2H),8.17-8.05 (m, 1H), 8.05-7.87 (m, 4H), 7.58-7.40 (m, 3H), 3.18 (d, J =4.1 Hz, 3H). DMSO >98 G2/AQ3 1340 ¹H NMR (300 MHz, DMSO) δ 9.67 (d, J =1.5 Hz, 1H), 8.80 (dt, J = 7.9, 1.9 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz,1H), 8.57-8.41 (m, 2H), 8.08 (dd, J = 6.1, 2.6 Hz, 1H), 7.99 (dd, J =8.6, 1.8 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 5.6 Hz, 1H),7.62- 7.44 (m, 4H), 3.17 (d, J = 4.5 Hz, 3H). DMSO >98 G2/AQ3 1341 ¹HNMR (300 MHz, DMSO) δ 9.66 (d, J = 1.5 Hz, 1H), 8.79 (dt, J = 7.9, 1.9Hz, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 8.65 (d, J = 1.9 Hz, 1H),8.61-8.53 (m, 1H), 8.35 (d, J = 1.6 Hz, 1H), 8.21 (dd, J = 8.7, 2.0 Hz,1H), 8.16 (d, J = 8.4 Hz, 1H), 7.92-7.80 (m, 3H), 7.59-7.48 (m, 2H),3.21 (d, J = 4.5 Hz, 3H). DMSO >98 G2/AQ3 1342 ¹H NMR (300 MHz, DMSO) δ9.66 (d, J = 1.6 Hz, 1H), 8.79 (dt, J = 8.0, 1.9 Hz, 1H), 8.73-8.61 (m,3H), 8.50 (s, 1H), 8.24 (dd, J = 8.7, 1.9 Hz, 1H), 8.04 (d, J = 8.4 Hz,1H), 7.96-7.82 (m, 3H), 7.60-7.50 (m, 2H), 3.21 (d, J = 4.4 Hz, 3H).DMSO >98 G2/AQ3 1343 2 HCl ¹H NMR (300 MHz, DMSO) δ 10.41 (brs, 1H),9.75 (d, J = 1.7 Hz, 1H), 9.24-9.19 (m, 1H), 9.01 (dd, J = 5.2, 1.5 Hz,1H), 8.90 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 8.7 Hz, 1H), 8.39 (dd, J =8.7, 1.7 Hz, 1H), 8.06-7.91 (m, 2H), 7.86 (d, J = 5.5 Hz, 1H), 7.66-7.52(m, 3H), 3.29 (d, J = 4.5 Hz, 3H). DMSO >98 G2/AQ3 1344 HCl ¹H NMR (300MHz, DMSO) δ 10.33 (brs, 1H), 9.78 (d, J = 2.0 Hz, 1H), 9.23 (d, J = 8.1Hz, 1H), 9.01 (d, J = 5.0 Hz, 1H), 8.73 (s, 1H), 8.48 (d, J = 8.6 Hz,1H), 8.14 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.95 (dd, J =8.1, 5.2 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.72-7.50 (m, 4H), 3.27 (d,J = 4.3 Hz, 3H). DMSO >98 G2/AQ3 1345 ¹H NMR (300 MHz, DMSO) δ 9.68 (d,J = 1.4 Hz, 1H), 8.85-8.77 (m, 1H), 8.77-8.62 (m, 3H), 8.40 (s, 1H),8.30 (dd, J = 8.7, 1.6 Hz, 1H), 8.14-7.95 (m, 4H), 7.91 (d, J = 8.7 Hz,1H), 7.63- 7.50 (m, 3H), 3.22 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3 1346¹H NMR (300 MHz, DMSO) δ 9.67 (d, J = 2.0 Hz, 1H), 8.80 (dt, J = 8.0,1.9 Hz, 1H), 8.69 (dd, J = 4.7, 1.7 Hz, 1H), 8.67-8.55 (m, 2H), 8.25(dd, J = 8.7, 1.8 Hz, 1H), 8.13-8.09 (m, 1H), 7.92- 7.77 (m, 4H), 7.71(d, J = 7.8 Hz, 1H), 7.67-7.47 (m, 4H), 7.47- 7.37 (m, 1H), 3.20 (d, J =4.4 Hz, 3H). DMSO >98 G2/AQ3 1347 ¹H NMR (300 MHz, DMSO) δ 9.68- 9.65(m, 1H), 8.79 (dt, J = 8.0, 1.9 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H),8.68-8.60 (m, 2H), 8.20 (dd, J = 8.7, 1.9 Hz, 1H), 7.99-7.95 (m, 2H),7.92-7.81 (m, 3H), 7.80-7.73 (m, 2H), 7.61-7.46 (m, 3H), 7.46-7.36 (m,1H), 3.20 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3 1348 ¹H NMR (300 MHz,DMSO) δ 9.66 (d, J = 1.5 Hz, 1H), 8.80 (dt, J = 7.9, 1.9 Hz, 1H), 8.70(dd, J = 4.7, 1.7 Hz, 1H), 8.55 (d, J = 4.6 Hz, 1H), 8.32 (d, J = 8.6Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.92- 7.84 (m, 3H), 7.60-7.50 (m,3H), 7.50-7.42 (m, 1H), 3.18 (d, J = 4.5 Hz, 3H). DMSO >98 G2/AQ3 1349 2HCl ¹H NMR (300 MHz, DMSO) δ 10.23 (brs, 1H), 9.67 (d, J = 2.1 Hz, 1H),9.04 (d, J = 7.7 Hz, 1H), 8.98-8.91 (m, 1H), 8.57 (d, J = 8.7 Hz, 1H),8.43 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.91-7.76 (m, 3H), 7.22-7.10 (m,2H), 3.85 (s, 3H), 3.31 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3 1350 2 HCl¹H NMR (300 MHz, DMSO) δ 10.48 (brs, 1H), 9.74 (d, J = 1.9 Hz, 1H), 9.19(d, J = 8.3 Hz, 1H), 9.07-8.97 (m, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.64(s, 1H), 8.36 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.16-8.06 (m, 2H), 7.95(dd, J = 8.1, 5.0 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 3.31 (d, J = 4.4Hz, 3H), 2.71 (s, 3H). DMSO >98 G2/AQ3 1351 2 HCl ¹H NMR (300 MHz, DMSO)δ 10.47 (brs, 1H), 9.73 (d, J = 1.3 Hz, 1H), 9.19 (d, J = 8.3 Hz, 1H),9.03-8.94 (m, 1H), 8.69-8.62 (m, 2H), 8.15-8.07 (m, 3H), 8.02-7.77 (m,3H), 3.29 (d, J = 4.3 Hz, 3H), 2.65 (s, 3H). DMSO >98 G2/AQ3 1352 2 HCl¹H NMR (300 MHz, DMSO) δ 10.44 (brs, 1H), 9.74 (s, 1H), 9.19 (d, J = 7.3Hz, 1H), 8.99 (d, J = 5.2 Hz, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.37 (s,1H), 8.03-7.90 (m, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.72-7.62 (m, 1H),7.53 (d, J = 9.6 Hz, 3H), 3.32 (d, J = 4.0 Hz, 3H). DMSO >98 G2/AQ3 13532 HCl ¹H NMR (300 MHz, DMSO) δ 10.48 (brs, 1H), 9.77 (s, 1H), 9.29- 9.23(m, 1H), 9.05-8.97 (m, 1H), 8.74-8.59 (m, 2H), 8.20- 8.08 (m, 1H),8.02-7.95 (m, 1H), 7.90 (s, 1H), 7.84-7.79 (m, 1H), 7.68-7.57 (m, 2H),3.35- 3.29 (m, 3H). DMSO >98 G2/AQ3 1354 2 HCl ¹H NMR (300 MHz, DMSO) δ10.35 (brs, 1H), 9.72 (d, J = 2.0 Hz, 1H), 9.21-9.11 (m, 1H), 8.98 (dd,J = 5.1, 1.4 Hz, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.59 (s, 1H), 8.09 (dd,J = 8.8, 1.7 Hz, 1H), 7.95-7.82 (m, 3H), 7.70- 7.60 (m, 2H), 3.30 (d, J= 4.4 Hz, 3H). DMSO >98 G2/AQ3 1355 2 HCl ¹H NMR (300 MHz, DMSO) δ 10.51(brs, 1H), 9.77 (d, J = 1.9 Hz, 1H), 9.22 (d, J = 8.2 Hz, 1H), 9.01 (dd,J = 5.1, 1.4 Hz, 1H), 8.69 (s, 1H), 8.40 (d, J = 8.7 Hz, 1H), 8.17 (dd,J = 8.7, 1.6 Hz, 1H), 7.96 (dd, J = 8.1, 5.2 Hz, 1H), 7.30-7.15 (m, 2H),7.10 (dd, J = 7.3, 1.9 Hz, 1H), 3.89 (s, 3H), 3.59 (s, 3H), 3.30 (d, J =4.5 Hz, 3H). DMSO >98 G2/AQ3 1356 2 HCl ¹H NMR (300 MHz, DMSO) δ 10.42(s, 1H), 9.71 (d, J = 1.8 Hz, 1H), 9.12 (d, J = 8.1 Hz, 1H), 8.97 (dd, J= 5.1, 1.5 Hz, 1H), 8.71 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.19 (dd, J= 8.7, 1.6 Hz, 1H), 7.90 (dd, J = 7.9, 5.1 Hz, 1H), 7.18-7.06 (m, 2H),7.01 (dd, J = 8.9, 3.1 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.30 (d, J =4.4 Hz, 3H). DMSO >98 G2/AQ3 1357 HCl ¹H NMR (300 MHz, DMSO) δ 10.21(brs, 1H), 9.63 (s, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.93 (d, J = 3.7 Hz,1H), 8.87 (s, 1H), 8.37 (d, J = 8.9 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H),7.91-7.78 (m, 1H), 7.05 (d, J = 2.1 Hz, 2H), 6.66- 6.58 (m, 1H), 3.87(s, 6H), 3.31 (d, J = 4.2 Hz, 3H). DMSO >98 G2/AQ3 1358 2 HCl ¹H NMR(300 MHz, DMSO) δ 10.43 (brs, 1H), 9.73 (d, J = 1.8 Hz, 1H), 9.17 (d, J= 8.2 Hz, 1H), 8.99 (dd, J = 5.0, 1.3 Hz, 1H), 8.69 (d, J = 8.6 Hz, 1H),8.49 (s, 1H), 8.05-7.88 (m, 2H), 7.71 (t, J = 7.9 Hz, 1H), 7.64-7.50 (m,1H), 7.50-7.33 (m, 2H), 3.32 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3 1359 2HCl ¹H NMR (300 MHz, DMSO) δ 10.29 (s, 1H), 9.70 (d, J = 1.7 Hz, 1H),9.14 (d, J = 8.3 Hz, 1H), 8.97 (dd, J = 5.1, 1.3 Hz, 1H), 8.63 (d, J =8.7 Hz, 1H), 8.58 (s, 1H), 8.15-8.04 (m, 1H), 7.90 (dd, J = 8.0, 5.1 Hz,1H), 7.75- 7.57 (m, 3H), 7.43-7.30 (m, 1H), 3.30 (d, J = 4.3 Hz, 3H).DMSO >98 G2/AQ3 1360 2 HCl ¹H NMR (300 MHz, DMSO) δ 10.41 (brs, 1H),9.73 (d, J = 1.9 Hz, 1H), 9.16 (d, J = 8.3 Hz, 1H), 8.98 (dd, J = 5.1,1.4 Hz, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.60 (s, 1H), 8.12-8.02 (m, 1H),8.00- 7.84 (m, 3H), 7.49-7.33 (m, 2H), 3.30 (d, J = 4.4 Hz, 3H).DMSO >98 G2/AQ3 1361 2 HCl ¹H NMR (300 MHz, DMSO) δ 10.39 (s, 1H), 9.71(d, J = 1.8 Hz, 1H), 9.17-9.08 (m, 1H), 8.97 (dd, J = 5.1, 1.5 Hz, 1H),8.64 (d, J = 8.7 Hz, 1H), 8.58 (s, 1H), 8.07 (dd, J = 8.6, 1.7 Hz, 1H),7.88 (dd, J = 8.1, 5.2 Hz, 1H), 7.70-7.58 (m, 2H), 7.46 (t, J = 7.6 Hz,1H), 7.33 (d, J = 7.4 Hz, 1H), 3.30 (d, J = 4.4 Hz, 3H), 2.43 (s, 3H).DMSO >98 G2/AQ3 1362 2 HCl ¹H NMR (300 MHz, DMSO) δ 10.37 (brs, 1H),9.70 (d, J = 1.7 Hz, 1H), 9.10 (d, J = 8.1 Hz, 1H), 8.96 (dd, J = 5.0,1.4 Hz, 1H), 8.62 (d, J = 8.7 Hz, 1H), 8.58 (s, 1H), 8.08 (dd, J = 8.6,1.6 Hz, 1H), 7.87 (dd, J = 7.9, 5.0 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H),7.39 (d, J = 8.0 Hz, 2H), 3.30 (d, J = 4.4 Hz, 3H), 2.40 (s, 3H).DMSO >98 G2/AQ3 1363 2 HCl ¹H NMR (300 MHz, DMSO) δ 9.82 (brs, 1H), 9.65(s, 1H), 9.14- 9.02 (m, 1H), 9.02-8.90 (m, 1H), 8.64-8.51 (m, 1H), 8.20(s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 8.00-7.85 (m, 3H), 7.85-7.66 (m, 2H),3.30 (s, 3H). DMSO >98 G2/AQ3 1364 HCl ¹H NMR (300 MHz, DMSO) δ 9.83(brs, 1H), 9.68-9.63 (m, 1H), 9.12-9.02 (m, 1H), 9.01-8.91 (m, 1H), 8.56(d, J = 9.2 Hz, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 8.19 (d, J = 8.7 Hz,1H), 8.13 (d, J = 9.3 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.93-7.84 (m,1H), 7.79 (t, J = 8.2 Hz, 1H), 3.28 (d, 4.5 Hz, 3H). DMSO >98 G2/AQ31365 2 HCl ¹H NMR (300 MHz, DMSO) δ 10.27 (brs, 1H), 9.72 (s, 1H), 9.23-9.10 (m, 1H), 8.98 (s, 1H), 8.77- 8.55 (m, 2H), 8.18-7.86 (m, 6H),3.34-3.27 (m, 3H). DMSO >98 G2/AQ3 1366 ¹H NMR (300 MHz, DMSO) δ 9.66(d, J = 2.0 Hz, 1H), 8.79 (dt, J = 7.9, 1.9 Hz, 1H), 8.69 (dd, J = 4.7,1.6 Hz, 1H), 8.65-8.53 (m, 2H), 8.22-8.12 (m, 3H), 7.92 (dd, J = 8.8,1.5 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.54(dd, J = 7.9, 4.8 Hz, 1H), 4.11 (s, 3H), 3.20 (d, J = 4.4 Hz, 3H).DMSO >98 G2/AQ3 1367 ¹H NMR (300 MHz, DMSO) δ 11.10 (s, 1H), 9.63 (d, J= 2.0 Hz, 1H), 8.85 (d, J = 1.7 Hz, 1H), 8.81-8.70 (m, 2H), 8.39 (dd, J= 8.9, 1.9 Hz, 1H), 8.15-8.02 (m, 5H), 7.60 (dd, J = 8.0, 4.8 Hz, 1H),2.65 (s, 3H), 2.61 (s, 3H). 1368 HCl ¹H NMR (300 MHz, DMSO) δ 9.72 (d, J= 1.8 Hz, 1H), 9.27-9.21 (m, 1H), 8.97 (dd, J = 5.3, 1.4 Hz, 1H), 8.50(dd, J = 8.8, 2.1 Hz, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.30 (d, J = 8.8Hz, 1H), 8.15- 8.09 (m, 2H), 8.09-7.98 (m, 3H), 3.55 (s, 3H), 2.65 (s,3H), 2.22 (s, 3H). DMSO >98 G2/AQ3 1369 HCl ¹H NMR (300 MHz, DMSO) δ11.16 (s, 1H), 9.67 (s, 1H), 9.20 (d, J = 8.2 Hz, 1H), 8.97 (d, J = 4.3Hz, 1H), 8.75 (s, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 8.8 Hz,1H), 8.02 (dd, J = 8.0, 5.5 Hz, 1H), 7.66-7.47 (m, 2H), 7.47- 7.34 (m,1H), 2.56 (s, 3H). DMSO >98 G2/AQ3 1370 2 HCl ¹H NMR (300 MHz, DMSO) δ10.17 (brs, 1H), 9.68 (d, J = 2.0 Hz, 1H), 9.06 (d, J = 8.0 Hz, 1H),8.95 (dd, J = 5.0, 1.4 Hz, 1H), 8.77 (s, 1H), 8.31 (s, 2H), 8.16 (d, J =2.1 Hz, 1H), 7.87 (dd, J = 7.8, 5.2 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H),7.61-7.47 (m, 2H), 7.19 (d, J = 1.4 Hz, 1H), 3.31 (d, J = 4.4 Hz, 3H).DMSO >98 G2/AQ3 1371 2 HCl ¹H NMR (300 MHz, DMSO) δ 10.28 (brs, 1H),9.71 (s, 1H), 9.16 (d, J = 7.9 Hz, 1H), 8.98 (d, J = 4.2 Hz, 1H), 8.67(d, J = 8.9 Hz, 1H), 8.45 (s, 1H), 8.01-7.83 (m, 2H), 7.68-7.50 (m, 2H),7.50- 7.35 (m, 1H), 3.31 (d, J = 4.1 Hz, 3H). DMSO >98 G2/AQ3 1372 HCl¹H NMR (300 MHz, DMSO) δ 9.72- 9.45 (m, 2H), 8.95 (d, J = 7.6 Hz, 1H),8.88 (d, J = 3.8 Hz, 1H), 8.49 (d, J = 8.5 Hz, 1H), 8.13 (s, 1H),7.91-7.75 (m, 3H), 7.53- 7.43 (m, 1H), 7.36-7.25 (m, 1H), 3.27 (d, J =4.3 Hz, 3H). DMSO >98 G2/AQ3 1373 2 HCl ¹H NMR (300 MHz, DMSO) δ 10.04(brs, 1H), 9.70 (s, 1H), 9.22- 9.07 (m, 1H), 8.93 (s, 1H), 8.62 (d, J =7.6 Hz, 1H), 8.55 (s, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.99- 7.79 (m, 2H),7.79-7.55 (m, 2H), 3.33-3.27 (m, 3H). DMSO >98 G2/AQ3 1374 2 HCl ¹H NMR(300 MHz, DMSO) δ 9.64 (s, 1H), 9.34 (brs, 1H), 9.06- 8.92 (m, 1H), 8.86(s, 1H), 8.50- 8.37 (m, 1H), 8.25 (s, 1H), 8.11- 7.95 (m, 1H), 7.85-7.74(m, 1H), 7.74-7.57 (m, 2H), 7.43- 7.29 (m, 1H), 3.28-3.21 (m, 3H).DMSO >98 G2/AQ3 1375 HCl ¹H NMR (300 MHz, DMSO) δ 9.63 (d, J = 1.6 Hz,1H), 9.38 (brs, 1H), 9.01-8.91 (m, 1H), 8.84 (dd, J = 5.0, 1.6 Hz, 1H),8.60 (s, 1H), 8.08 (s, 2H), 7.76 (dd, J = 7.9, 5.1 Hz, 1H), 7.64-7.38(m, 2H), 3.26 (d, J = 3.7 Hz, 3H). DMSO >98 G2/AQ3 1376 HCl ¹H NMR (300MHz, DMSO) δ 9.88 (brs, 1H), 9.65 (s, 1H), 9.18- 8.99 (m, 1H), 8.90 (s,1H), 8.70 (s, 1H), 8.31-8.03 (m, 2H), 7.94- 7.77 (m, 2H), 7.77-7.57 (m,1H), 3.28 (s, 3H). DMSO >98 G2/AQ3 1377 2 HCl ¹H NMR (300 MHz, DMSO) δ10.33 (s, 1H), 9.67 (s, 1H), 9.10 (d, J = 7.8 Hz, 1H), 9.02 (s, 1H),8.92 (d, J = 5.0 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 8.8 Hz,1H), 8.03-7.76 (m, 3H), 3.31 (s, 3H). DMSO >98 G2/AQ3 1378 2 HCl ¹H NMR(300 MHz, DMSO) δ 9.66 (d, J = 1.7 Hz, 1H), 9.56-9.34 (m, 1H), 9.26-9.10(m, 1H), 9.05 (d, J = 4.7 Hz, 1H), 8.44 (s, 1H), 8.19 (dd, J = 8.1, 5.7Hz, 1H), 7.95 (d, J = 11.5 Hz, 1H), 7.63-7.45 (m, 2H), 7.45-7.26 (m,1H), 3.19 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3 1379 HCl ¹H NMR (300 MHz,DMSO) δ 9.67- 9.59 (m, 1H), 9.38 (d, J = 8.3 Hz, 1H), 9.22-9.10 (m, 1H),9.03 (d, J = 4.9 Hz, 1H), 8.37 (s, 1H), 8.16 (dd, J = 8.1, 5.6 Hz, 1H),7.89 (d, J = 11.6 Hz, 1H), 7.78 (td, J = 8.9, 6.6 Hz, 1H), 7.54-7.36 (m,1H), 7.30 (td, J = 8.3, 2.0 Hz, 1H), 3.18 (d, J = 4.4 Hz, 3H). DMSO >98G2/AQ3 1380 2 HCl ¹H NMR (300 MHz, DMSO) δ 9.72 (d, J = 1.6 Hz, 1H),9.25-9.14 (m, 1H), 8.99 (dd, J = 5.2, 1.5 Hz, 1H), 8.51 (s, 1H), 8.44(d, J = 8.7 Hz, 1H), 8.26-8.11 (m, 1H), 7.94 (dd, J = 8.0, 5.2 Hz, 1H),7.65-7.49 (m, 2H), 7.49-7.29 (m, 1H), 3.69 (s, 6H). DMSO >98 G2/AQ3 13812 HCl ¹H NMR (300 MHz, DMSO) δ 9.71 (s, 1H), 9.18 (d, J = 8.0 Hz, 1H),8.98 (d, J = 5.1 Hz, 1H), 8.49- 8.36 (m, 2H), 8.16 (d, J = 8.8 Hz, 1H),7.99-7.86 (m, 1H), 7.86- 7.72 (m, 1H), 7.46 (t, J = 10.2 Hz, 1H), 7.29(t, J = 8.5 Hz, 1H), 3.69 (s, 6H). DMSO >98 G2/AQ3 1382 HCl ¹H NMR (300MHz, DMSO) δ 10.25 (brs, 1H), 9.66 (d, J = 1.6 Hz, 1H), 9.04 (d, J = 3.2Hz, 1H), 8.94 (dd, J = 5.0, 1.6 Hz, 1H), 8.70 (s, 1H), 8.23 (d, J = 8.8Hz, 1H), 8.16 (dd, J = 8.7, 1.5 Hz, 1H), 7.84 (dd, J = 8.0, 5.1 Hz, 1H),7.71 (dd, J = 8.0, 1.4 Hz, 1H), 7.65-7.55 (m, 2H), 3.90 (s, 3H), 3.29(d, J = 4.5 Hz, 3H), 2.64 (s, 3H). DMSO >98 G2/AQ3 1383 2 HCl ¹H NMR(300 MHz, DMSO) δ 10.18 (brs, 1H), 9.68 (d, J = 1.8 Hz, 1H), 9.17 (d, J= 8.0 Hz, 1H), 8.99 (dd, J = 5.2, 1.4 Hz, 1H), 8.86 (s, 1H), 8.31 (d, J= 8.7 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.97 (dd, J = 8.0, 5.3 Hz, 1H),7.64-7.49 (m, 2H), 7.49-7.34 (m, 1H), 4.06-3.92 (m, 2H), 3.73 (t, J =5.5 Hz, 2H), 3.33 (s, 3H). DMSO >98 G2/AQ3 1384 2 HCl ¹H NMR (300 MHz,DMSO) δ 10.18 (brs, 1H), 9.67 (d, J = 1.6 Hz, 1H), 9.14 (d, J = 3.1 Hz,1H), 8.99 (dd, J = 5.2, 1.5 Hz, 1H), 8.80 (s, 1H), 8.29 (d, J = 8.7 Hz,1H), 8.18 (d, J = 8.7 Hz, 1H), 7.95 (dd, J = 8.2, 5.2 Hz, 1H), 7.79 (td,J = 8.9, 6.6 Hz, 1H), 7.50 (ddd, J = 11.6, 9.3, 2.6 Hz, 1H), 7.33 (td, J= 8.3, 2.3 Hz, 1H), 4.08-3.94 (m, 3H), 3.73 (t, J = 5.5 Hz, 3H), 3.32(s, 3H). DMSO >98 G2/AQ3 1385 2 HCl ¹H NMR (300 MHz, DMSO) δ 10.33 (brs,1H), 9.70 (d, J = 1.7 Hz, 1H), 9.15 (d, J = 8.2 Hz, 1H), 8.99 (dd, J =5.2, 1.5 Hz, 1H), 8.81 (s, 1H), 8.33 (d, J = 8.7 Hz, 1H), 8.18 (d, J =8.7 Hz, 1H), 7.95 (dd, J = 8.1, 5.2 Hz, 1H), 7.81 (td, J = 8.9, 6.6 Hz,1H), 7.49 (ddd, J = 11.5, 9.3, 2.5 Hz, 1H), 7.32 (td, J = 8.5, 2.2 Hz,1H), 3.96-3.78 (m, 2H), 3.48 (t, J = 6.1 Hz, 2H), 3.27 (s, 3H),2.14-1.93 (m, 2H). DMSO >98 G2/AQ3 1386 2 HCl ¹H NMR (300 MHz, DMSO) δ9.73 (s, 1H), 9.17 (d, J = 8.4 Hz, 1H), 8.99 (s, 1H), 8.52 (s, 1H), 8.43(d, J = 8.8 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 8.02-7.90 (m, 1H),7.87-7.78 (m, 1H), 7.57-7.38 (m, 1H), 7.38-7.24 (m, 1H), 4.31-4.18 (m,4H), 2.08 (s, 4H). DMSO >98 G2/AQ3 1387 2 HCl ¹H NMR (300 MHz, DMSO) δ9.68 (d, J = 1.7 Hz, 1H), 9.17 (d, J = 8.3 Hz, 1H), 8.99 (dd, J = 5.2,1.5 Hz, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.24-8.12 (m, 2H), 7.97 (dd, J =8.0, 5.2 Hz, 1H), 7.81 (td, J = 8.9, 6.6 Hz, 1H), 7.49 (ddd, J = 11.6,9.3, 2.5 Hz, 1H), 7.30 (td, J = 8.4, 2.1 Hz, 1H), 4.16 (brs, 4H), 1.80(brs, 6H). DMSO >98 G2/AQ3 1388 2 HCl ¹H NMR (300 MHz, DMSO) δ 9.70 (d,J = 1.7 Hz, 1H), 9.26 (d, J = 8.3 Hz, 1H), 9.01 (dd, J = 5.3, 1.4 Hz,1H), 8.37-8.19 (m, 2H), 8.15 (d, J = 8.7 Hz, 1H), 8.02 (dd, J = 8.1, 5.3Hz, 1H), 7.81 (td, J = 8.9, 6.5 Hz, 1H), 7.48 (ddd, J = 11.6, 9.3, 2.6Hz, 1H), 7.30 (td, J = 8.4, 2.3 Hz, 1H), 4.23-4.12 (m, 4H), 3.90-3.80(m, 4H). DMSO >98 G2/AQ3 1389 2 HCl ¹H NMR (300 MHz, DMSO) δ 9.68 (d, J= 1.7 Hz, 1H), 9.17 (d, J = 8.2 Hz, 1H), 8.99 (dd, J = 5.2, 1.5 Hz, 1H),8.34 (d, J = 8.7 Hz, 1H), 8.27-8.13 (m, 2H), 7.97 (dd, J = 8.1, 5.4 Hz,1H), 7.67-7.48 (m, 2H), 7.41 (ddd, J = 14.7, 9.9, 4.9 Hz, 1H), 4.16(brs, 4H), 1.80 (brs, 6H). DMSO >98 G2/AQ3 1390 2 HCl ¹H NMR (300 MHz,DMSO) δ 9.70 (d, J = 1.8 Hz, 1H), 9.26 (d, J = 8.3 Hz, 1H), 9.01 (dd, J= 5.3, 1.4 Hz, 1H), 8.36-8.23 (m, 2H), 8.18 (d, J = 8.7 Hz, 1H), 8.03(dd, J = 8.0, 5.4 Hz, 1H), 7.64- 7.46 (m, 2H), 7.46-7.29 (m, 1H),4.23-4.16 (m, 4H), 3.35 (d, J = 4.7 Hz, 4H). DMSO >98 G2/AQ3 1391 2 HCl¹H NMR (300 MHz, DMSO) δ 9.68 (d, J = 1.7 Hz, 1H), 9.18 (d, J = 8.2 Hz,1H), 9.00 (dd, J = 5.2, 1.2 Hz, 1H), 8.62 (s, 1H), 8.39 (d, J = 8.7 Hz,1H), 8.21 (d, J = 8.8 Hz, 1H), 7.98 (dd, J = 8.0, 5.2 Hz, 1H), 7.64-7.47(m, 2H), 7.46- 7.27 (m, 1H), 4.26 (t, J = 5.2 Hz, 2H), 3.85 (t, J = 5.3Hz, 2H), 3.72 (s, 3H), 3.33 (s, 3H). DMSO >98 G2/AQ3 1392 2 HCl ¹H NMR(300 MHz, DMSO) δ 9.67 (d, J = 1.7 Hz, 1H), 9.15 (d, J = 8.1 Hz, 1H),8.99 (d, J = 4.1 Hz, 1H), 8.56 (s, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.17(d, J = 8.7 Hz, 1H), 7.96 (dd, J = 8.1, 5.2 Hz, 1H), 7.86-7.70 (m, 1H),7.55-7.40 (m, 1H), 7.30 (td, J = 8.5, 2.2 Hz, 1H), 4.36-4.18 (m, 2H),3.88- 3.77 (m, 2H), 3.72 (s, 3H), 3.33 (s, 3H). DMSO >98 G2/AQ3 1393 2HCl ¹H NMR (300 MHz, DMSO) δ 9.70 (d, J = 3.7 Hz, 1H), 9.24-9.06 (m,1H), 8.99 (dd, J = 5.1, 1.5 Hz, 1H), 8.52 (s, 1H), 8.40 (d, J = 8.7 Hz,1H), 8.30-8.14 (m, 1H), 7.93 (dd, J = 8.0, 5.2 Hz, 1H), 7.63-7.46 (m,2H), 7.46-7.25 (m, 1H), 4.22-4.11 (m, 2H), 3.73 (s, 3H), 3.59 (t, J =5.9 Hz, 2H), 2.10-1.92 (m, 2H). DMSO >98 G2/AQ3 1394 2 HCl ¹H NMR (300MHz, DMSO) δ 9.68 (d, J = 1.7 Hz, 1H), 9.11 (d, J = 8.3 Hz, 1H), 8.97(dd, J = 5.1, 1.5 Hz, 1H), 8.46 (s, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.17(d, J = 8.8 Hz, 1H), 7.90 (dd, J = 8.1, 5.2 Hz, 1H), 7.80 (td, J = 8.9,6.6 Hz, 1H), 7.47 (ddd, J = 11.6, 9.3, 2.6 Hz, 1H), 7.29 (td, J = 8.4,2.1 Hz, 1H), 4.22-4.08 (m, 2H), 3.72 (s, 3H), 3.59 (t, J = 5.9 Hz, 2H),2.10- 1.94 (m, 2H). DMSO >98 G2/AQ3 1395 HCl ¹H NMR (300 MHz, DMSO) δ9.97- 9.66 (m, 2H), 9.66-9.58 (m, 1H), 9.17-9.05 (m, 1H), 8.99 (dd, J =5.2, 1.5 Hz, 1H), 8.66 (d, J = 8.6 Hz, 1H), 8.50 (s, 1H), 8.01-7.88 (m,2H), 7.62 (ddd, J = 9.1, 6.1, 3.1 Hz, 1H), 7.58- 7.36 (m, 2H). DMSO >98G2/AQ3 1396 HCl ¹H NMR (300 MHz, DMSO) δ 9.70 (d, J = 1.8 Hz, 1H), 9.16(d, J = 8.3 Hz, 1H), 8.98 (d, J = 3.9 Hz, 1H), 8.58-8.42 (m, 2H), 8.00-7.82 (m, 2H), 7.69-7.38 (m, 3H), 3.69 (s, 6H). DMSO >98 G2/AQ3 1397 HCl¹H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 9.63 (d, J = 1.8 Hz, 1H), 9.11(d, J = 3.0 Hz, 1H), 9.04 (s, 1H), 8.96 (dd, J = 5.1, 1.4 Hz, 1H), 8.41(dd, J = 8.8, 1.6 Hz, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 3.2Hz, 2H), 7.90 (d, J = 8.4 Hz, 3H), 3.34 (t, J = 17.1 Hz, 3H). DMSO >98AQ4 1398 HCl ¹H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 9.65 (d, J = 1.7Hz, 1H), 9.06 (d, J = 7.9 Hz, 1H), 8.99-8.90 (m, 2H), 8.44 (d, J = 7.2Hz, 1H), 8.23-8.17 (m, 3H), 7.94-7.76 (m, 3H), 3.32 (d, J = 4.5 Hz, 3H).DMSO >98 AQ4 1399 HCl ¹H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 9.65 (d, J= 2.1 Hz, 1H), 9.10-9.00 (m, 1H), 8.96 (dd, J = 5.1, 1.5 Hz, 1H), 8.65(s, 1H), 8.26-8.17 (m, 1H), 8.16- 8.07 (m, 1H), 7.90 (dd, J = 7.8, 5.3Hz, 1H), 7.77-7.69 (m, 1H), 7.68-7.55 (m, 3H), 3.29 (d, J = 4.6 Hz, 3H).DMSO >98 AQ4 1400 HCl ¹H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 9.63 (d, J= 1.7 Hz, 1H), 9.04-8.85 (m, 2H), 8.63 (s, 1H), 8.12 (q, J = 8.7 Hz,2H), 7.83 (dd, J = 7.8, 4.9 Hz, 1H), 7.38- 7.25 (m, 2H), 7.25-7.17 (m,1H), 3.92 (s, 3H). DMSO >98 AQ4 1401 HCl ¹H NMR (400 MHz, DMSO) δ 10.05(s, 1H), 9.64 (d, J = 1.7 Hz, 1H), 9.04 (d, J = 7.6 Hz, 1H), 8.99-8.92(m, 1H), 8.89 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.33- 8.20 (m, 2H),8.16 (d, J = 3.6 Hz, 1H), 7.94-7.84 (m, 1H), 7.81- 7.68 (m, 1H), 3.32(d, J = 4.5 Hz, 3H). DMSO >98 AQ4 1402 2 HCl ¹H NMR (400 MHz, DMSO) δ10.30 (s, 1H), 9.68 (d, J = 1.8 Hz, 1H), 9.15-9.05 (m, 1H), 8.97 (dd, J= 5.1, 1.4 Hz, 1H), 8.52 (s, 1H), 8.10 (s, 1H), 7.96-7.82 (m, 1H),7.67-7.55 (m, 1H), 7.42- 7.26 (m, 3H), 3.31 (d, J = 4.5 Hz, 3H), 2.40(s, 3H). DMSO >98 AQ5 1403 2 HCl ¹H NMR (400 MHz, DMSO) δ 9.87 (s, 1H),9.59 (d, J = 1.5 Hz, 1H), 9.00-8.89 (m, 2H), 8.42 (s, 1H), 7.93-7.80 (m,2H), 7.62-7.54 (m, 1H), 7.49-7.36 (m, 3H), 3.30 (d, J = 4.6 Hz, 3H),2.32 (s, 3H). DMSO >98 AQ5 1404 2 HCl ¹H NMR (400 MHz, DMSO) δ 10.19 (s,1H), 9.68-9.61 (m, 1H), 9.05-8.98 (m, 1H), 8.94 (dd, J = 5.0, 1.6 Hz,1H), 8.48 (d, J = 5.7 Hz, 1H), 8.02 (s, 1H), 7.91-7.82 (m, 1H),7.59-7.50 (m, 2H), 7.43-7.36 (m, 2H), 3.31 (d, J = 4.6 Hz, 3H), 2.40 (s,3H). DMSO >98 AQ5 1405 2 HCl ¹H NMR (400 MHz, DMSO) δ 10.11 (s, 1H),9.69-9.61 (m, 1H), 9.11-9.02 (m, 1H), 8.95 (dd, J = 5.1, 1.5 Hz, 1H),8.52 (s, 1H), 8.05 (s, 1H), 7.89 (dd, J = 8.1, 5.1 Hz, 1H), 7.68-7.56(m, 1H), 7.48-7.38 (m, 1H), 7.33- 7.25 (m, 1H), 3.31 (d, J = 4.6 Hz,3H), 2.33 (s, 3H). DMSO >98 AQ5 1406 2 HCl ¹H NMR (400 MHz, DMSO) δ10.03 (s, 1H), 9.63 (dd, J = 2.2, 0.7 Hz, 1H), 9.09-9.00 (m, 1H), 8.95(dd, J = 5.1, 1.6 Hz, 1H), 8.48 (s, 1H), 8.00 (s, 1H), 7.89 (dd, J =7.9, 5.2 Hz, 1H), 7.54- 7.35 (m, 3H), 3.30 (d, J = 4.6 Hz, 3H), 2.33 (s,3H). DMSO >98 AQ5 1407 2 HCl ¹H NMR (400 MHz, DMSO) δ 10.09 (s, 1H),9.63 (d, J = 1.6 Hz, 1H), 9.08-8.98 (m, 1H), 8.95 (dd, J = 5.1, 1.5 Hz,1H), 8.46 (s, 1H), 7.98 (s, 1H), 7.87 (dd, J = 8.1, 5.1 Hz, 1H), 7.64(ddt, J = 16.8, 14.3, 5.3 Hz, 2H), 7.40- 7.30 (m, 1H), 3.30 (d, J = 4.6Hz, 3H), 2.41 (s, 3H). DMSO >98 AQ5 1408 2 HCl ¹H NMR (400 MHz, DMSO) δ9.92 (s, 1H), 9.61 (d, J = 1.6 Hz, 1H), 9.03-8.97 (m, 1H), 8.94 (dd, J =5.1, 1.5 Hz, 1H), 8.42 (s, 1H), 7.93 (s, 1H), 7.87 (dd, J = 8.1, 5.0 Hz,1H), 7.44-7.36 (m, 1H), 7.33-7.23 (m, 2H), 3.29 (d, J = 4.6 Hz, 3H),2.41 (s, 3H). DMSO >98 AQ5 1409 2 HCl ¹H NMR (400 MHz, DMSO) δ 10.11 (s,1H), 9.64 (d, J = 2.2 Hz, 1H), 9.10-9.03 (m, 1H), 8.96 (dd, J = 5.1, 1.5Hz, 1H), 8.49 (s, 1H), 8.05-7.94 (m, 3H), 7.94- 7.88 (m, 1H), 7.88-7.82(m, 1H), 7.77 (t, J = 7.7 Hz, 1H), 3.31 (d, J = 4.5 Hz, 3H), 2.40 (s,3H). DMSO >98  AQ5 1410 3 HCl ¹H NMR (400 MHz, DMSO) δ 10.22 (s, 1H),9.67 (d, J = 1.6 Hz, 1H), 9.14-9.07 (m, 1H), 8.97 (dd, J = 5.1, 1.5 Hz,1H), 8.52 (s, 1H), 8.10-8.00 (m, 3H), 7.91 (dd, J = 7.9, 5.3 Hz, 1H),7.75- 7.67 (m, 2H), 3.31 (d, J = 4.5 Hz, 3H), 2.39 (s, 3H). DMSO >98 AQ51411 2 HCl ¹H NMR (400 MHz, DMSO) δ 10.20-9.85 (m, 1H), 9.58 (s, 1H),8.94-8.85 (m, 2H), 8.38 (s, 1H), 7.88-7.76 (m, 2H), 7.54- 7.44 (m, 1H),7.24-7.16 (m, 2H), 7.12 (td, J = 7.4, 0.9 Hz, 1H), 3.76 (s, 3H), 3.31(d, J = 4.5 Hz, 3H), 2.24 (s, 3H). DMSO >98% AQ5 1412 2 HCl ¹H NMR (400MHz, DMSO) δ 10.20 (s, 1H), 9.69-9.61 (m, 1H), 9.01 (d, J = 7.8 Hz, 1H),8.93 (dd, J = 5.0, 1.6 Hz, 1H), 8.49 (s, 1H), 8.06 (s, 1H), 7.83 (dd, J= 8.0, 5.1 Hz, 1H), 7.51- 7.41 (m, 1H), 7.13-7.05 (m, 1H), 7.05-6.95 (m,2H), 3.81 (d, J = 10.8 Hz, 3H), 3.31 (d, J = 4.6 Hz, 3H), 2.41 (s, 3H).DMSO >98% AQ5 1413 2 HCl ¹H NMR (400 MHz, DMSO) δ 10.09 (s, 1H), 9.60(s, 1H), 9.00- 8.88 (m, 2H), 8.42 (s, 1H), 7.94 (s, 1H), 7.86-7.78 (m,1H), 7.48- 7.39 (m, 2H), 7.16-7.06 (m, 2H), 3.85 (s, 3H), 3.31 (d, J =4.6 Hz, 3H), 2.43 (s, 3H). DMSO >98% AQ5 1414 2 HCl ¹H NMR (400 MHz,DMSO) δ 10.02 (s, 1H), 9.63 (s, 1H), 9.05- 8.91 (m, 2H), 8.36 (s, 1H),8.10- 7.99 (m, 1H), 7.91-7.80 (m, 1H), 7.59-7.50 (m, 2H), 7.44- 7.32 (m,2H), 3.27 (d, J = 4.5 Hz, 3H), 2.45 (s, 3H). DMSO >98 AQ5 1415 2 HCl ¹HNMR (400 MHz, DMSO) δ 10.01 (s, 1H), 9.65 (s, 1H), 9.10- 8.99 (m, 1H),8.97 (d, J = 5.0 Hz, 1H), 8.41 (s, 1H), 8.09 (s, 1H), 7.97-7.83 (m, 1H),7.61-7.41 (m, 2H), 7.31 (td, J = 8.4, 2.2 Hz, 1H), 3.26 (d, J = 4.5 Hz,3H), 2.35 (s, 3H). DMSO >98 AQ5 1416 2 HCl ¹H NMR (400 MHz, DMSO) δ10.01-9.69 (m, 1H), 9.61 (s, 1H), 8.94 (m, J = 5.0 Hz, 2H), 8.36 (s,1H), 7.99 (s, 1H), 7.92- 7.81 (m, 1H), 7.71-7.57 (m, 2H), 7.41-7.31 (m,1H), 3.26 (d, J = 4.5 Hz, 3H), 2.47 (s, 3H). DMSO >98 AQ5 1417 2 HCl ¹HNMR (400 MHz, DMSO) δ 9.90 (s, 1H), 9.63 (d, J = 1.8 Hz, 1H), 9.08-8.89(m, 2H), 8.40 (s, 1H), 8.02 (s, 1H), 7.92-7.81 (m, 1H), 7.44-7.25 (m,3H), 3.27 (d, J = 4.5 Hz, 3H), 2.49 (s, 3H). DMSO >98 AQ5 1418 2 HCl ¹HNMR (400 MHz, DMSO) δ 9.99 (s, 1H), 9.62 (s, 1H), 8.95 (d, J = 5.0 Hz,2H), 8.27 (s, 1H), 8.11- 7.99 (m, 1H), 7.89-7.80 (m, 1H), 7.53-7.45 (m,1H), 7.24 (dd, J = 7.4, 1.7 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.12 (td,J = 7.4, 0.9 Hz, 1H), 3.74 (d, J = 8.9 Hz, 3H), 3.26 (d, J = 4.6 Hz,3H), 2.28 (s, 3H). DMSO >98 AQ5 1419 2 HCl ¹H NMR (400 MHz, DMSO) δ10.30 (s, 1H), 9.72 (d, J = 1.6 Hz, 1H), 9.20-9.10 (m, 1H), 8.98 (dd, J= 5.1, 1.5 Hz, 1H), 8.45 (s, 1H), 8.21 (s, 1H), 7.91 (dd, J = 8.0, 5.1Hz, 1H), 7.48-7.40 (m, 1H), 7.08-7.01 (m, 3H), 3.84 (s, 3H), 3.26 (d, J= 4.5 Hz, 3H), 2.45 (s, 3H). DMSO >98 AQ5 1420 2 HCl ¹H NMR (400 MHz,DMSO) δ 10.08-9.71 (m, 1H), 9.58 (d, J = 2.0 Hz, 1H), 8.96-8.83 (m, 2H),8.31 (s, 1H), 7.91 (s, 1H), 7.87- 7.79 (m, 1H), 7.47-7.39 (m, 2H), 7.10(d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 3.27 (d, J = 4.5 Hz, 3H), 2.47 (s,3H). DMSO >98 AQ5 1421 2 HCl 1H NMR (400 MHz, DMSO) δ 9.69- 9.63 (m,1H), 9.10-8.93 (m, 3H), 8.12 (d, J = 8.4 Hz, 1H), 7.90-7.82 (m, 2H),7.63-7.58 (m, 1H), 7.56-7.43 (m, 1H), 7.30-7.22 (m, 1H), 3.35 (d, j =4.6 Hz, 3H), 2.73 (s, 3H). DMSO >98 AQ4 1422 2 HCl 1H NMR (400 MHz,DMSO) δ 9.62 (s, 1H), 8.95 (d, J = 5.0 Hz, 3H), 8.03 (s, 1H), 7.85 (t, J= 9.9 Hz, 2H), 7.44-7.34 (m, 1H), 7.17 (dd, J = 8.2, 2.2 Hz, 2H), 3.34(d, J = 4.5 Hz, 3H), 2.73 (s, 3H). DMSO >98 AQ4 1423 2 HCl 1H NMR (400MHz, DMSO) δ 9.62 (d, J = 2.1 Hz, 1H), 9.00-8.75 (m, 3H), 8.08-7.99 (m,1H), 7.99-7.93 (m, 1H), 7.93-7.79 (m, 3H), 7.79-7.73 (m, 2H), 3.34 (d, J= 4.5 Hz, 3H), 2.70 (s, 3H). DMSO >98 AQ4 1424 2 HCl 1H NMR (400 MHz,DMSO) δ 9.61 (s, 1H), 8.99-8.63 (m, 3H), 8.07- 7.98 (m, 3H), 7.89-7.78(m, 2H), 7.65-7.59 (m, 2H), 3.33 (d, J = 4.5 Hz, 3H), 2.70 (s, 3H).DMSO >98 AQ4 1425 3 HCl ¹H NMR (400 MHz, DMSO) δ 10.49 (s, 1H), 9.56 (s,1H), 9.19 (s, 1H), 8.95 (d, J = 5.3 Hz, 1H), 8.83 (d, J = 5.5 Hz, 1H),8.73 (d, J = 6.4 Hz, 1H), 8.41 (d, J = 5.6 Hz, 1H), 8.26 (s, 1H), 8.09(s, 1H), 8.02-7.91 (m, 2H), 7.85 (s, 1H), 7.78-7.68 (m, 1H), 7.61- 7.51(m, 1H), 7.48-7.36 (m, 2H), 5.36 (s, 2H). DMSO >98 Method AQ3 1426 3 HCl¹H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 9.67 (d, J = 1.8 Hz, 1H), 9.32(dd, J = 5.8, 4.1 Hz, 1H), 8.97 (dd, J = 5.4, 1.4 Hz, 1H), 8.75 (d, J =8.7 Hz, 1H), 8.35 (t, J = 7.9 Hz, 1H), 8.24 (d, J = 13.5 Hz, 1H), 8.03(dd, J = 8.1, 5.4 Hz, 1H), 7.92 (dd, J = 13.5, 4.8 Hz, 2H), 7.85-7.73(m, 2H), 7.53-7.43 (m, 1H), 7.36-7.25 (m, 1H), 5.40 (d, J = 5.6 Hz, 2H),2.85 (s, 3H). DMSO >98 Method AQ3 1427 3 HCl ¹H NMR (400 MHz, DMSO) δ10.42 (s, 1H), 9.64 (d, J = 1.7 Hz, 1H), 9.26 (d,.J = 8.1 Hz, 1H), 8.95(dd, J = 5.3, 1.4 Hz, 1H), 8.71 (d, J = 8.7 Hz, 1H), 8.30 (d, J = 18.0Hz, 2H), 8.04-7.84 (m, 3H), 7.74 (dd, J = 7.8, 6.0 Hz, 2H), 7.62-7.33(m, 3H), 5.38 (d, J = 5.5 Hz, 2H), 2.84 (s, 3H). DMSO >98 Method AQ31428 3 HCl ¹H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 9.63 (d, J = 1.6 Hz,1H), 9.24 (d, J = 8.1 Hz, 1H), 8.95 (dd, J = 5.3, 1.4 Hz, 1H), 8.69 (d,J = 3.7 Hz, 1H), 8.41- 8.22 (m, 2H), 8.09 (dd, J = 8.7, 1.8 Hz, 1H),8.01-7.84 (m, 4H), 7.74 (d, J = 7.8 Hz, 1H), 7.46- 7.33 (m, 2H), 5.36(d, J = 5.5 Hz, 2H), 2.83 (s, 3H). DMSO >98 Method AQ3 1429 3 HCl ¹H NMR(400 MHz, DMSO) δ 10.21 (s, 1H), 9.62 (s, 1H), 9.19 (d, J = 7.8 Hz, 1H),8.93 (d, J = 4.6 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 8.26 (dd, J = 28.0,20.1 Hz, 2H), 8.04-7.80 (m, 3H), 7.72 (d, J = 7.8 Hz, 1H), 7.64-7.50 (m,2H), 7.46-7.33 (m, 1H), 5.33 (d, J = 5.3 Hz, 2H), 2.81 (s, 3H). DMSO >98Method AQ3 1430 3 HCl ¹H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 9.66 (d, J= 1.8 Hz, 1H), 9.31 (d, J = 8.2 Hz, 1H), 8.96 (dd, J = 5.4, 1.4 Hz, 1H),8.73 (d, J = 8.7 Hz, 1H), 8.33 (t, J = 7.9 Hz, 1H), 8.23 (s, 1H), 8.03(dd, J = 8.1, 5.4 Hz, 1H), 7.93 (dd, J = 11.7, 8.3 Hz, 2H), 7.76 (d, J =7.9 Hz, 1H), 7.70-7.60 (m, 1H), 7.54-7.35 (m, 2H), 5.38 (d, J = 5.5 Hz,2H), 2.85 (s, 3H). DMSO >98 Method AQ3 1431 3 HCl ¹H NMR (400 MHz, DMSO)δ 10.15 (s, 1H), 9.61 (s, 1H), 9.22 (t, J = 7.3 Hz, 1H), 8.98-8.90 (m,1H), 8.65 (dd, J = 8.6, 3.0 Hz, 1H), 8.36-8.26 (m, 2H), 8.13 (dd, J =8.7, 1.9 Hz, 1H), 8.05-7.95 (m, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.76-7.64(m, 3H), 7.43-7.33 (m, 1H), 5.33 (s, 2H), 2.82 (s, 3H). DMSO >98 MethodAQ3 1432 3 HCl ¹H NMR (400 MHz, DMSO) δ 10.26 (s, 1H), 9.62 (d, J = 1.8Hz, 1H), 9.23 (d, J = 8.2 Hz, 1H), 8.94 (dd, J = 5.4, 1.5 Hz, 1H), 8.78(s, 1H), 8.30 (t, J = 7.9 Hz, 1H), 8.20-8.15 (m, 1H), 8.10 (d, J = 8.7Hz, 1H), 8.00 (dd, J = 7.9, 5.3 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H),7.80-7.71 (m, 2H), 7.59-7.50 (m, 1H), 7.47-7.35 (m, 2H), 5.35 (d, J =5.5 Hz, 2H), 2.82 (s, 3H). DMSO >98 Method AQ3 1433 3 HCl ¹H NMR (400MHz, DMSO) δ 10.39 (s, 1H), 9.61 (d, J = 1.7 Hz, 1H), 9.19 (d, J = 8.2Hz, 1H), 9.01 (d, J = 1.8 Hz, 1H), 8.93 (dd, J = 5.3, 1.5 Hz, 1H), 8.38(dd, J = 8.8, 1.9 Hz, 1H), 8.29 (t, J = 7.9 Hz, 1H), 8.09 (d, J = 8.7Hz, 1H), 7.97 (dd, J = 8.1, 5.3 Hz, 1H), 7.92-7.80 (m, 3H), 7.72 (d, J =7.3 Hz, 1H), 7.66-7.57 (m, 1H), 7.35-7.26 (m, 1H), 5.36 (d, J = 5.5 Hz,2H), 2.81 (s, 3H). DMSO >98 Method AQ3 1434 3 HCl ¹H NMR (400 MHz, DMSO)δ 10.45 (s, 1H), 9.60 (d, J = 1.9 Hz, 1H), 9.19 (d, J = 8.2 Hz, 1H),9.01-8.89 (m, 2H), 8.36-8.25 (m, 2H), 8.10 (d, J = 8.7 Hz, 1H),8.05-7.94 (m, 3H), 7.88 (dd, J = 12.8, 3.4 Hz, 1H), 7.72 (d, J = 7.8 Hz,1H), 7.46-7.35 (m, 2H), 5.36 (d, J = 5.5 Hz, 2H), 2.32 (s, 3H). DMSO >98Method AQ3 1435 3 HCl ¹H NMR (400 MHz, DMSO) δ 10.28 (s, 1H), 9.63 (d, J= 1.8 Hz, 1H), 9.24 (d, J = 8.2 Hz, 1H), 8.95 (d, 1H), 8.83 (s, 1H),8.30 (t, J = 7.9 Hz, 1H), 8.19 (dd, J = 8.7, 1.8 Hz, 1H), 8.11 (d, J =8.7 Hz, 1H), 8.00 (dd, J = 8.1, 5.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H),7.73 (d, J = 7.8 Hz, 1H), 7.64- 7.51 (m, 2H), 7.46-7.37 (m, 1H), 5.36(d, J = 5.5 Hz, 2H), 2.82 (s, 3H). DMSO >98 Method AQ3 1436 3 HCl ¹H NMR(400 MHz, DMSO) δ 10.02 (s, 1H), 9.56 (d, J = 1.6 Hz, 1H), 9.06 (d, J =8.0 Hz, 1H), 8.88 (dd, J = 5.2, 1.5 Hz, 1H), 8.75 (s, 1H), 8.25-8.13 (m,2H), 8.04 (d, J = 8.7 Hz, 1H), 7.89 (dd, J = 7.8, 5.3 Hz, 1H), 7.79 (d,J = 8.0 Hz, 1H), 7.70-7.60 (m, 2H), 7.53-7.44 (m, 1H), 7.38 (ddd, J =12.2, 8.4, 3.5 Hz, 1H), 5.27 (d, J = 5.3 Hz, 2H), 2.77 (s, 3H). DMSO >98Method AQ3 1437 3 HCl ¹H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 9.60 (d, J= 1.7 Hz, 1H), 9.19 (d, J = 8.1 Hz, 1H), 8.93 (dd, J = 5.4, 1.5 Hz, 1H),8.75 (s, 1H), 8.29 (t, J = 7.9 Hz, 1H), 8.17-8.05 (m, 2H), 7.98 (dd, J =8.0, 5.4 Hz, 1H), 7.83 (ddd, J = 15.5, 8.4, 6.0 Hz, 2H), 7.72 (d, J =7.8 Hz, 1H), 7.54- 7.44 (m, 1H), 7.38-7.28 (m, 1H), 5.33 (d, J = 5.5 Hz,2H), 2.81 (s, 3H). DMSO >98 Method AQ3 1438 4 HCl ¹H NMR (400 MHz, DMSO)δ 10.45 (s, 1H), 9.62 (d, J = 1.7 Hz, 1H), 9.21 (d, J = 8.1 Hz, 1H),9.03 (d, J = 1.7 Hz, 1H), 8.93 (dd, J = 5.3, 1.4 Hz, 1H), 8.39- 8.26 (m,2H), 8.15-8.04 (m, 2H), 8.00-7.81 (m, 3H), 7.76- 7.59 (m, 2H), 5.36 (d,J = 5.5 Hz, 2H), 2.82 (s, 3H). DMSO >98 Method AQ3 1439 3 HCl ¹H NMR(400 MHz, DMSO) δ 10.29 (s, 1H), 9.53 (d, J = 1.8 Hz, 1H), 9.12 (d, J =8.0 Hz, 1H), 8.93 (dd, J = 5.3, 1.4 Hz, 1H), 8.78 (d, J = 2.5 Hz, 2H),8.31 (t, J = 7.8 Hz, 1H), 8.13 (q, J = 8.7 Hz, 2H), 8.04-7.89 (m, 2H),7.87-7.68 (m, 2H), 7.50 (ddd, J = 11.6, 9.3, 2.6 Hz, 1H), 7.33 (td, J =8.3, 1.9 Hz, 1H), 5.30 (d, J = 5.4 Hz, 2H). DMSO >98 Method AQ3 1440 2HCl ¹H NMR (400 MHz, DMSO) 10.41 (s, 1H), 9.63 (d, J = 1.7 Hz, 1H), 9.15(d, J = 8.1 Hz, 1H), 8.97 (dd, J = 5.2, 1.4 Hz, 1H), 8.83 (s, 1H), 8.20(s, 2H), 7.97 (dd, J = 8.0, 5.3 Hz, 1H), 7.73- 7.56 (m, 2H), 7.54-7.28(m, 4H), 5.03 (d, J = 5.7 Hz, 2H). DMSO >98 Method AQ3 1441 2 HCl ¹H NMR(400 MHz, DMSO) δ 9.59 (d, J = 1.6 Hz, 1H), 9.07-8.94 (m, 2H), 8.84 (s,1H), 8.76 (s, 1H), 8.22-8.13 (m, 2H), 7.96 (dd, J = 8.0, 5.3 Hz, 1H),7.66 (ddd, J = 9.2, 6.1, 3.2 Hz, 1H), 7.53-7.32 (m, 2H), 1.69 (s, 9H).DMSO >98 Method AQ3 1442 2 HCl ¹H NMR (400 MHz, DMSO) δ 9.93 (s, 1H),9.62 (d, J = 1.6 Hz, 1H), 9.06-8.87 (m, 2H), 8.39 (s, 1H), 8.06-7.98 (m,3H), 7.87 (dd, J = 8.0, 5.1 Hz, 1H), 7.77--7.67 (m, 2H), 3.26 (d, J =4.6 Hz, 3H), 2.45 (s, 3H). DMSO >98 Method AQ3 1443 2 HCl ¹H NMR (400MHz, DMSO) δ 9.98 (s, 1H), 9.64 (s, 1H), 8.99 (dd, J = 27.3, 6.4 Hz,2H), 8.41 (s, 1H), 8.10-7.93 (m, 3H), 7.88 (dd, J = 7.7, 6.0 Hz, 2H),7.76 (t, J = 7.8 Hz, 1H), 3.27 (d, J = 4.5 Hz, 3H), 2.46 (s, 3H).DMSO >98 Method AQ3 1444 2 HCl ¹H NMR (400 MHz, DMSO) δ 9.76- 9.69 (m,1H), 9.37 (t, J = 5.4 Hz, 1H), 8.99 (dd, J = 11.7, 7.5 Hz, 1H), 8.81(dt, J = 7.9, 4.0 Hz, 1H), 8.70 (t, J = 7.3 Hz, 1H), 8.52 (d, J = 9.2Hz, 1H), 8.35-8.27 (m, 1H), 8.10 (dd, J = 12.8, 7.3 Hz, 1H), 8.01-7.90(m, 2H), 7.77-7.71 (m, 1H), 7.50-7.37 (m, 3H), 7.06-7.01 (m, 1H), 5.19(t, J = 17.9 Hz, 2H), 3.88 (s, 3H). DMSO >98 Method AQ3, F, G2 (reflux)1445 2 HCl 1H NMR (DMSO-d6) ppm 9.73 (s, 1H), 9.37 (brd, J = 8.08 Hz,1H), 8.97 (brd, J = 5.24 Hz, 1H), 8.77 (brs, 1H), 8.20 (d, J = 8.48 Hz,1H), 8.10-8.07 (brm, 1H), 7.63- 7.55 (brm, 2H), 7.47 (d, J = 8.48 Hz,1H), 7.32 (brm, 1H), 3.20 (d, J = 4.20 Hz, 3H), 2.65 (s, 3H). The 1H of2HCl was not observed. DMSO >98 AQ6 1446 3 HCl 1H NMR (DMSO-d6) ppm 9.73(d, J = 1.76 Hz, zH), 9.39 (brd, J = 8.16 Hz, 1H), 8.98 (dd, J = 5.44,1.20 Hz, 1H), 8.80 (brs, 1H), 8.22 (d, J = 8.48 Hz, 1H), 8.12-8.08 (brm,1H), 7.57-7.51 (m, 1H), 7.46-7.35 (m, 4H), 3.21 (d, J = 4.32 Hz, 3H),2.55 (s, 3H). The 1H of 3HCl was not observed. DMSO >98 AQ6 1447 3 HCl1H NMR (DMSO-d6) ppm 9.72 (d, J = 1.68 Hz, 1H), 9.26 (brd, J = 8.48 Hz,1H), 8.91 (dd, J = 5.28, 1.40 Hz, 1H), 8.69 (brs, 1H), 8.18 (d, J = 8.56Hz, 1H), 8.00-7.96 (brm, 1H), 7.53-7.49 (m, 2H), 7.44 (d, J = 8.56 Hz,1H), 7.38- 7.33 (m, 2H), 3.20 (d, J = 4.40 Hz, 3H), 2.63 (s, 3H). The 1Hof 3HCl was not observed. DMSO >98 AQ6 1448 2 HCl 1H NMR (DMSO-d6) ppm9.73 (d, J = 1.44 Hz, 1H), 9.36 (brd, J = 7.88 Hz, 1H), 8.96 (d, J =5.04 Hz, 1H), 8.77 (brs, 1H), 8.21 (d, J = 8.56 Hz, 1H), 8.07 (brm, 1H),7.48 (d, J = 8.56 Hz, 1H), 7.38- 7.32 (m, 1H), 7.27-7.22 (m, 2H), 3.20(d, J = 4.4 Hz, 3H), 2.65 (s, 3H). The 1H of 2HCl was not observed.DMSO >98 AQ6 1449 3 HCl 1H NMR (DMSO-d6) ppm 9.73 (d, J = 1.72 Hz, 1H),9.32 (brd, J = 7.56 Hz, 1H), 8.94 (brd, J = 5.48 Hz, 1H), 8.74 (brs,1H), 8.20 (d, J = 8.56 Hz, 1H), 8.08-8.02 (m, 1H), 7.60-7.54 (m, 1H),7.47 (d, J = 7.35-7.27 (m, 3H), 3.20 (d, J = 4.4 Hz, 3H), 2.65 (s, 3H).The 1H of 3HCl was not observed. DMSO >98 AQ6 1450 2 HCl 1H NMR(DMSO-d6) ppm 9.74 (d, J = 1.76 Hz, 1H), 9.37 (brd, J = 8.16 Hz, 1H),8.97 (brdd, J = 5.44, 1.24 Hz, 1H), 8.79 (brs, 1H), 8.22 (d, J = 8.52Hz, 1H), 8.10-8.06 (brm, 1H), 7.48-7.35 (m, 4H), 3.21 (d, J = 4.36 Hz,3H), 2.56 (brs, 3H). The 1H of 2HCl was not observed. DMSO >98 AQ6 14513 HCl 1H NMR (DMSO-d6) ppm 9.74 (d, J = 1.52 Hz, 1H), 9.37 (d, J = 8.08Hz, 1H), 8.97 (dd, J = 5.54, 1.16 Hz, 1H), 8.80 (brs, 1H), 8.23 (d, J =8.52 Hz, 1H), 8.10- 8.07 (m, 1H), 7.60-7.53 (m, 1H), 7.48 (d, J = 8.52Hz, 1H), 7.41- 7.36 (m, 1H), 7.30-7.26 (m, 1H), 3.21 (d, J = 4.36 Hz,3H), 2.56 (s, 3H). The 1H of 3HCl was not observed. DMSO >98 AQ6 1452 3HCl 1H NMR (DMSO-d6) ppm 9.73 (d, J = 1.68 Hz, 1H), 9.26 (brd, J = 7.8Hz, 1H), 8.91 (brdd, J = 5.28, 1.36 Hz, 1H), 8.71 (brs, 1H), 8.21 (d, J= 8.52 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.99-7.95 (m, 1H), 7.69 (d,8.4 Hz, 2H), 7.46 (d, J = 8.52 Hz, 1H), 3.20 (d, J = 4.4 Hz, 3H), 2.63(s, 3H). The 1H of 3HCl was not observed. DMSO >98 AQ6 1453 2 HCl 1H NMR(DMSO-d6) ppm 9.73 (d, J = 1.72 Hz, 1H), 9.33 (brd, J = 7.64 Hz, 1H),8.95 (brd, J = 5.28 Hz, 1H), 8.76 (brs, 1H), 8.22 (d, J = 8.48 Hz, 1H),8.05 (brm, J = 7.64, 5.28 Hz, 1H), 7.98-7.93 (m, 2 H), 7.84-7.81 (m,1H), 7.74 (dd, J = 7.84, 7.76 Hz, 1H), 7.49 (d, J = 8.84 Hz, 1H), 3.21(d, J = 4.4 Hz, 3H), 2.63 (s, 3H). The 1H of 2HCl was not observed.DMSO >98 AQ6 1454 2 HCl ¹H NMR (DMSO-d₆) ppm 9.72 (d, J = 1.76 Hz, 1H),9.42 (brd, J = 8.00 Hz, 1H), 9.00 (d, J = 5.52 Hz, 1H), 8.83 (bsr, 1H),8.22 (d, J = 8.56 Hz, 1H), 8.13 (brm, 1H), 7.55-7.51 (m, 2H), 7.48-7.43(m, 4H), 3.21 (brd, J = 4.16 Hz, 3H), 2.64 (s, 3H). The 1H of 2HCl wasnot observed. DMSO >98 AQ6 1455 2 HCl ¹H NMR (DMSO-d₆) ppm 9.72 (s, 1H),9.33 (d, J = 8.24 Hz, 1H), 8.96 (d, J = 5.40 Hz, 1H), 8.75 (brs, 1H),8.17 (d, J = 8.60 Hz, 1H), 8.06 (brm, 1H), 7.45 (d, J = 8.80 Hz, 1H),7.40 (d, J = 8.64 Hz, 2H), 7.08 (d, J = 8.64 Hz, 2H), 3.84 (s, 3H), 3.20(d, J = 4.20 Hz, 3H), 2.66 (s, 3H). The 1H of 2HCl was not observed.DMSO >98 AQ6 1456 2 HCl ¹H NMR (DMSO-d₆) ppm 9.72 (d, J = 1.64 Hz, 1H),9.38 (d, J = 8.04 Hz, 1H), 8.98 (dd, J = 5.48, 1.24 Hz, 1H), 8.79 (brs,1H), 8.20 (d, J = 8.52 Hz, 1H), 8.12-8.09 (m, 1H), 7.48-7.42 (m, 2H),7.04-6.97 (m, 3H), 3.82 (s, 3H), 3.21 (d, J = 4.28 Hz, 3H), 2.65 (s,3H). The 1H of 2HCl was not observed. DMSO >98 AQ6 1457 2 HCl ¹H NMR(DMSO-d₆) ppm 9.71 (d, J = 1.32 Hz, 1H), 9.40 (d, J = 7.64 Hz, 1H), 8.99(dd, J = 5.52, 1.16 Hz, 1H), 3.32 (brs, 1H), 8.17 (d, J = 8.48 Hz, 1H),8.13 (m, 1H), 7.47-7.43 (m, 1H), 7.37 (d, J = 8.48 Hz, 1H), 7.22-7.16(m, 2H), 7.11-7.07 (m, 1H), 3.73 (s, 3H), 3.21 (d, J = 4.12 Hz, 3H),2.47 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 AQ6 1458 2 HCl¹H NMR (DMSO-d₆) ppm 9.57 (d, J = 1.88 Hz, 1H), 8.93 (dd, J = 4.88, 1.56Hz, 1H), 8.87 (brd, J = 6.52 Hz, 1H), 7.95 (d, J = 8.36 Hz, 1H), 7.84(d, J = 8.36 Hz, 1H), 7.81 (m, 1H), 7.34 (d, J = 8.72 Hz, 2H), 7.11 (d,J = 8.72 Hz, 2H), 3.84 (s, 3H), 3.34 (d, J = 4.56 Hz, 3H), 2.72 (s, 3H).The 1H of 2HCl and NH— were not observed. DMSO >98 AQ6 1459 2 HCl ¹H NMR(DMSO-d₆) ppm 9.59 (s, 1H), 8.94 (dd, J = 4.92, 1.48 Hz, 1H), 8.89 (br,1H), 7.98 (d, J = 8.48 Hz, 1H), 7.86 (d, J = 8.48 Hz, 1H), 7.82 (m, 1H),7.46 (t, J = 7.96 Hz, 1H), 7.06-7.03 (m, 1H), 6.98-6.94 (m, 2H), 3.83(s, 3H), 3.34 (d, J = 4.56 Hz, 3H), 2.72 (s, 3H). The 1H of 2HCl and NH—were not observed. DMSO >98 AQ6 1460 ¹H NMR (300 MHz, DMSO) δ 9.60 (s,1H), 8.84-8.57 (m, 3H), 8.30 (d, J = 7.0 Hz, 1H), 8.18 (d, J = 8.8 Hz,1H), 8.12-7.93 (m, 4H), 7.85 (dd, J = 8.7, 1.5 Hz, 1H), 7.60-7.46 (m,1H), 4.85-4.58 (m, 1H), 1.37 (d, J = 6.5 Hz, 6H). DMSO   100 AQ1 366(M + 1) Method A (Formic acid) 1461 HCl 1H NMR (300 MHz, DMSO) δ 9.81(s, 1H), 9.60 (s, 1H), 8.95 (s, 3H), 8.39 (d, J = 3.9 Hz, 1H), 8.19 (s,1H), 7.96-7.73 (m, 3H), 7.68- 7.55 (m, 1H), 7.39-7.25 (m, 1H), 4.99-4.81(m, 1H), 1.42 (d, J = 6.5 Hz, 6H). DMSO   100 AQ1 359 (M + 1) Method A(Formic acid) 1462 ¹H NMR (300 MHz, DMSO) δ 9.43 (s, 1H), 8.75-8.47 (m,3H), 8.29 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 7.1 Hz, 1H), 7.72-7.54 (m,2H), 7.48 (dd, J = 7.8, 4.9 Hz, 1H), 7.44-7.32 (m, 1H), 7.30-7.12 (m,1H), 3.32 (s, 3H), 3.16 (d, J = 4.3 Hz, 3H). DMSO 100 AQ1 349 (M + 1)Method A (Formic acid) 1463 1H NMR (300 MHz, DMSO) δ 9.68 (dd, J = 2.1,0.8 Hz, 1H), 8.86- 8.78 (m, 1H), 8.74 (dd, J = 4.8, 1.7 Hz, 1H),8.34-8.25 (m, 2H), 8.09-8.02 (m, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.60(ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.09 (d, J = 8.9 Hz, 2H), 4.31 (s, 3H),3.83 (s, 3H). DMSO    99 Method AQ2 344.0 (M + 1) Method C 1464 1H NMR(300 MHz, DMSO) δ 9.67 (d, J = 2.1 Hz, 1H), 8.82 (d, J = 7.9 Hz, 1H),8.74 (dd, J = 4.8, 1.7 Hz, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.36 (dd, J =8.8, 2.2 Hz, 1H), 8.15-7.94 (m, 5H), 7.60 (ddd, J = 8.0, 4.8, 0.8 Hz,1H), 4.31 (s, 3H). DMSO    99 Method AQ2 338.9 (M + 1) Method C 1465 2HCl 1H NMR (300 MHz, DMSO) δ 9.71 (d, J = 1.8 Hz, 1H), 9.15 (d, J = 8.0Hz, 1H), 8.90 (dd, J = 5.2, 1.4 Hz, 1H), 8.58 (s, J = 1.8 Hz, 1H), 8.48(d, J = 1.6 Hz, 1H), 8.43 (dd, J = 8.7, 2.2 Hz, 1H), 8.32 (dd, J = 7.8,0.9 Hz, 1H), 8.28 (dd, J = 8.2, 2.2 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H),7.92 (dd, J = 8.0, 5.2 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 4.34 (s, 3H).DMSO    99 Method AQ2 359.0 (M + 1) Method C 1466 2 HCl 1H NMR (300 MHz,DMSO) δ 9.71 (d, J = 2.0 Hz, 1H), 9.12 (dd, J = 8.0, 1.4 Hz, 1H), 8.89(dd, J = 5.2, 1.5 Hz, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.42 (dd, J = 8.8,2.2 Hz, 1H), 8.34 (d, J = 9.0 Hz, 2H), 8.14 (dd, J = 9.2, 2.4 Hz, 3H),7.88 (dd, J = 7.8, 5.5 Hz, 1H), 4.34 (s, 3H). DMSO    99 Method AQ2359.0 (M + 1) Method C 1467 2 HCl 1H NMR (300 MHz, DMSO) δ 9.36 (s, 1H),9.00 (d, J = 6.5 Hz, 2H), 8.78 (d, J = 4.5 Hz, 2H), 8.58 (s, 1H), 8.06(s, 2H), 7.75 (dd, J = 15.6, 8.9 Hz, 1H), 7.47 (ddd, J = 11.7, 9.4, 2.6Hz, 1H), 7.31 (td, J = 8.4, 2.7 Hz, 1H), 3.22 (d, J = 4.2 Hz, 3H). DMSO   99 Method AQ2 349.6 (M + 1) Method C 1468 3 HCl 1H NMR (300 MHz,DMSO) δ 9.97 (s, 1H), 9.63 (d, J = 1.6 Hz, 1H), 9.04 (d, J = 7.0 Hz,1H), 8.94 (dd, J = 5.1, 1.5 Hz, 1H), 8.76 (d, J = 0.7 Hz, 1H), 8.41-8.05(m, 4H), 7.89 (dd, J = 7.1, 4.8 Hz, 1H), 7.59 (ddd, J = 7.1, 4.9, 1.8Hz, 1H), 3.27 (d, J = 4.3 Hz, 3H). DMSO    99 Method AQ2 332.4 (M + 1)Method C 1469 2 HCl 1H NMR (300 MHz, DMSO) δ 10.04 (s, 1H), 9.65 (d, J =1.5 Hz, 1H), 9.06 (d, J = 7.3 Hz, 1H), 8.95 (dd, J = 5.1, 1.5 Hz, 1H),8.71 (s, 1H), 8.19 (s, 2H), 7.89 (dd, J = 7.6, 5.1 Hz, 1H), 7.76- 7.61(m, 2H), 7.42 (td, J = 7.9, 0.9 Hz, 1H), 3.27 (d, J = 4.4 Hz, 3H). DMSO   95 Method AQ2 365.3 (M + 1) Method C 1470 2 HCl 1H NMR (300 MHz,DMSO) δ 10.03 (s, 1H), 9.63 (d, J = 1.5 Hz, 1H), 9.04 (d, J = 7.9 Hz,1H), 8.94 (dd, J = 5.1, 1.5 Hz, 1H), 8.68 (s, 1H), 8.16 (s, 2H), 7.88(dd, J = 7.6, 5.1 Hz, 1H), 7.74 (t, J = 8.5 Hz, 1H), 7.67 (dd, J = 10.8,2.0 Hz, 1H), 7.51 (dd, J = 8.3, 1.6 Hz, 1H), 3.27 (d, J = 4.4 Hz, 3H).DMSO    94 Method AQ2 365.3 (M + 1) Method C 1471 2 HCl 1H NMR (300 MHz,DMSO) δ 9.95 (s, 1H), 9.64 (d, J = 1.6 Hz, 1H), 9.07 (d, J = 7.9 Hz,1H), 8.94 (dd, J = 5.1, 1.5 Hz, 1H), 8.75 (s, 1H), 8.18 (s, 2H), 8.09(d, J = 11.1 Hz, 1H), 7.92 (d, J = 4.0 Hz, 3H), 3.27 (d, J = 4.4 Hz,3H). DMSO    96 Method AQ2 356.4 (M + 1) Method C 1472 2 HCl 1H NMR (300MHz, DMSO) δ 10.01 (s, 1H), 9.63 (d, J = 1.5 Hz, 1H), 9.03 (d, J = 7.8Hz, 1H), 8.94 (dd, J = 5.1, 1.5 Hz, 1H), 8.73 (s, 1H), 8.25-8.12 (m,3H), 7.93-7.76 (m, 4H), 7.63 (d, J = 0.8 Hz, 1H), 3.28 (d, J = 4.4 Hz,3H). DMSO    95 Method AQ2 374.4 (M + 1) Method C 1473 2 HCl 1H NMR (300MHz, DMSO) δ 9.97 (s, 1H), 9.61 (d, J = 2.1 Hz, 1H), 8.98 (d, J = 4.6Hz, 1H), 8.93 (dd, J = 5.1, 1.5 Hz, 1H), 8.68- 8.60 (m, 1H), 8.13 (d, J= 6.1 Hz, 2H), 7.85 (dd, J = 7.7, 5.2 Hz, 1H), 7.63 (t, J = 8.3 Hz, 1H),7.37- 7.23 (m, 2H), 3.27 (d, J = 4.5 Hz, 3H), 2.56 (s, J = 5.2 Hz, 3H).DMSO    95 Method AQ2 377.5 (M + 1) Method C 1474 2 HCl 1H NMR (300 MHz,DMSO) δ 9.98 (s, 1H), 9.64 (d, J = 1.6 Hz, 1H), 9.06 (d, J = 8.8 Hz,1H), 8.94 (dd, J = 5.1, 1.5 Hz, 1H), 8.75 (s, 1H), 8.26-8.11 (m, 2H),8.04- 7.85 (m, 5H), 3.35 (s, 3H), 3.27 (d, J = 4.1 Hz, 3H). DMSO    96Method AQ2 409.5 (M + 1) Method C 1475 2 HCl 1H NMR (300 MHz, DMSO) δ10.25 (s, 1H), 9.63 (d, J = 1.6 Hz, 1H), 9.00 (d, J = 7.1 Hz, 1H), 8.93(dd, J = 5.0, 1.5 Hz, 1H), 8.79 (s, 1H), 8.31 (dd, J = 8.8, 1.5 Hz, 1H),8.17 (d, J = 8.5 Hz, 1H), 7.84 (dd, J = 7.5, 4.3 Hz, 1H), 7.51 (d, J =1.8 Hz, 1H), 7.40 (dd, J = 8.2, 1.9 Hz, 1H), 7.09 (d, J = 3.1 Hz, 1H),6.10 (s, 2H), 3.29 (d, J = 4.3 Hz, 3H). DMSO    99 Method AQ2 357.5(M + 1) Method C 1476 2 HCl 1H NMR (300 MHz, DMSO) δ 10.26 (s, 1H), 9.63(d, J = 1.6 Hz, 1H), 9.01 (d, J = 3.6 Hz, 1H), 8.93 (dd, J = 5.0, 1.5Hz, 1H), 8.77 (s, 1H), 8.31 (dd, J = 8.8, 1.4 Hz, 1H), 8.18 (d, J = 8.6Hz, 1H), 7.84 (dd, J = 6.9, 5.8 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.39(dd, J = 8.4, 2.3 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 4.30 (s, 4H), 3.29(d, J = 4.4 Hz, 3H). DMSO    99 Method AQ2 371.5 (M + 1) Method C 1477 2HCl 1H NMR (300 MHz, DMSO) δ 10.19 (s, 1H), 9.61 (d, J = 1.6 Hz, 1H),8.98 (d, J = 8.8 Hz, 1H), 8.93 (dd, J = 5.0, 1.5 Hz, 1H), 8.82 (s, 1H),8.35 (dd, J = 8.8, 1.3 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.85 (dd, J =8.1, 5.2 Hz, 1H), 7.76-7.66 (m, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.31 (d,J = 7.7 Hz, 1H), 3.69 (t, J = 7.0 Hz, 2H), 3.31 (d, J = 4.4 Hz, 3H),2.84 (t, J = 7.0 Hz, 2H). DMSO    99 Method AQ2 357.5 (M + 1) Method C1478 2 HCl 1H NMR (300 MHz, DMSO) δ 10.11 (s, 1H), 9.60 (d, J = 1.9 Hz,1H), 8.93 (dd, J = 10.3, 5.4 Hz, 2H), 8.80 (d, J = 0.6 Hz, 1H), 8.34(dd, J = 8.0, 0.5 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.88- 7.75 (m, 3H),7.40 (d, J = 8.3 Hz, 2H), 3.65 (t, J = 6.9 Hz, 2H), 3.30 (d, J = 4.4 Hz,3H), 2.79 (t, J = 6.9 Hz, 2H). DMSO    99 Method AQ2 357.5 (M + 1)Method C 1479 2 HCl 1H NMR (300 MHz, DMSO) δ 10.27 (s, 1H), 9.62 (d, J =1.5 Hz, 1H), 8.99 (s, 1H), 8.96-8.33 (m, 2H), 8.37 (d, J = 8.9 Hz, 1H),8.18 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.85 (s, 1H), 7.70(d, J = 8.5 Hz, 2H), 3.30 (d, J = 4.3 Hz, 3H), 1.74 (s, 6H). DMSO    99Method AQ2 380.5 (M + 1) Method C 1480 2 HCl 1H NMR (300 MHz, DMSO) δ10.23 (s, 1H), 9.62 (d, J = 1.8 Hz, 1H), 9.02 (d, J = 6.6 Hz, 1H), 8.93(dd, J = 5.0, 1.5 Hz, 1H), 8.88 (d, J = 0.5 Hz, 1H), 8.33 (d, J = 8.5Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.86 (dd, J= 7.4, 5.1 Hz, 1H), 7.75 (dd, J = 8.5, 1.8 Hz, 1H), 7.60 (d, J = 8.5 Hz,1H), 3.29 (d, J = 4.3 Hz, 3H). DMSO    99 Method AQ2 393.4 (M + 1)Method C 1481 1H NMR (300 MHz, DMSO) δ 9.63 (d, J = 1.4 Hz, 1H),8.81-8.73 (m, 1H), 3.68 (dd, J = 4.7, 1.7 Hz, 1H), 8.61 (d, J = 4.3 Hz,1H), 8.45 (s, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 8.7 Hz, 2H),7.77-7.61 (m, 3H), 7.53 (dd, J = 7.9, 4.8 Hz, 1H), 7.40 (t, J = 7.6 Hz,1H), 3.15 (d, J = 4.3 Hz, 3H). DMSO    99 Method AQ2, followed byhydrolysis with 30% H₂O₂ and NaOH in ethanol 374.5 (M + 1) Method C 14822 HCl 1H NMR (300 MHz, DMSO) δ 10.60 (s, 1H), 10.29 (s, 1H), 9.62 (d, J= 1.5 Hz, 1H), 9.00 (d, J = 7.1 Hz 1H), 8.92 (dd, J = 4.9, 1.4 Hz, 1H),8.76 (s, 1H), 8.29 (d, J = 8.9 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.84(dd, J = 7.8, 4.8 Hz, 1H), 7.79-7.68 (m, 2H), 6.95 (d, J = 8.0 Hz, 1H),3.57 (s, 2H), 3.29 (d, J = 4.3 Hz, 3H). DMSO    94 Method AQ1, exceptthat dioxane water was replaced with DME/water/ EtOH in the microwave at120° C. for 10 min 368.5 (M + 1) Method C 1483 2 HCl 1H NMR (300 MHz,DMSO) δ 10.67 (s, 1H), 9.60 (d, J = 2.4 Hz, 1H), 8.99-8.88 (m, 2H), 8.73(d, J = 1.0 Hz, 1H), 8.27 (d, J = 9.2 Hz, 1H), 8.10 (d, J = 7.5 Hz, 1H),7.83 (dd, J = 6.9, 4.3 Hz, 1H), 7.40 (q, J = 3.3 Hz, 2H), 7.20 (s, 1H),3.56 (s, 2H), 3.29 (d, J = 4.1 Hz, 3H). DMSO    99 Method AQ1, exceptthat dioxane water was replaced with DME/water/ EtOH in the microwave at120° C. for 10 min 368.5 (M + 1) Method C 1484 2 HCl 1H NMR (300 MHz,DMSO) δ 10.12 (s, 1H), 9.61 (d, J = 1.9 Hz, 1H), 9.04-8.89 (m, 2H), 8.84(d, J = 1.2 Hz, 1H), 8.36 (dd, J = 8.7, 1.3 Hz, 1H), 8.14 (d, J = 8.1Hz, 1H), 7.94-7.78 (m, 3H), 7.50 (d, J = 8.3 Hz, 2H), 4.49 (s, 2H),3.39-3.23 (m, 6H). DMSO    99 Method AQ1, except that dioxane water wasreplaced with DME/water/ EtOH in the microwave at 120° C. for 10 min357.5 (M + 1) Method C 1485 1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H),8.76 (td, J = 8.0, 1.6 Hz, 1H), 871 (dd, J = 4.8, 1.6 Hz, 1H), 8.37 (s,1H), 7.81 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.59-7.54 (m,1H), 7.43 (t, J = 8.0 Hz, 1H), 7.06-6.98 (m, 3H), 3.82 (s, 3H). DMSO   95 Method G1, AQ1 377.0 379.0 (M + 1) Method B (NH₄HCO₃) 1486 2HCl1H-NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 9.38 (d, J = 8.4 Hz, 1H),9.15 (d, J = 5.2 Hz, 1H), 8.69 (d, J = 1.6 Hz, 1H), 8.41 (dd, J = 8.8,2.0 Hz, 1H), 8.29- 8.26 (m, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.50-7.41 (m,3H), 7.11- 7.08 (m, 1H), 4.80-4.76 (m, 1H), 3.66-3.57 (m, 2H), 3.50 (s,3H), 3.44 (s, 3H), 1.35 (d, J = 6.4 Hz, 3H). DMSO    95 Method G1, AQ1401.1 (M + 1) Method B (NH₄HCO₃) 1487 2HCl 1H-NMR (400 MHz, CD3OD): δ9.55 (s, 1H), 8.92 (d, J = 4.9 Hz, 1H), 8.89 (dt, J = 8.2, 1.8 Hz, 1H),8.62 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.83(dd, J = 8.0, 5.0 Hz, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.43 (s, 2H), 7.10(d, J = 7.6 Hz, 1H), 4.01 (s, 2H), 3.46 (s, 3H), 3.35 (s, 3H), 1.37 (s,6H). MeOD    95 Method G1, AQ1 415.1 (M + 1) Method B (NH₄HCO₃) 14882HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.65 (s, 1H), 9.04 (d,J = 6.9 Hz, 1H), 8.99-8.87 (m, 2H), 8.39 (d, J = 9.2 Hz, 1H), 8.24 (d, J= 8.2 Hz, 1H), 7.86 (s, 1H), 7.47-7.43 (m, 3H), 7.05 (d, J = 6.8 Hz,1H), 4.26-4.22 (m, 2H), 3.77-3.73 (m, 2H), 3.56- 3.50 (m, 2H), 3.32 (d,J = 4.3 Hz, 3H), 1.15 (t, J = 7.0 Hz, 3H). DMSO    95 Method G1, AQ1400.9 (M + 1) Method B (NH₄HCO₃) 1489 1H-NMR (400 MHz, DMSO-d6): δ 9.68(s, 1H), 8.81-8.78 (m, 2H), 8.71 (d, J = 3.6 Hz, 1H), 8.54 (s, 1H), 8.32(d, J = 1.2 Hz, 1H), 7.57 (dd, J = 7.6, 4.8 Hz, 1H), 7.46-7.42 (m, 3H),7.04-7.01 (m, 1H), 3.88 (s, 3H), 3.19 (d, J = 4.0 Hz, 3H). DMSO    95Method G1, AQ1 377.1, 379.1 (M + 1) Method B (NH₄HCO₃) 1490 2HCl 1H-NMR(400 MHz, DMSO-d6): δ 10.50 (brs, 1H), 9.68 (d, J = 2.0 Hz, 1H), 9.09(d, J = 8.0 Hz, 1H), 8.96 (dd, J = 5.2, 1.2 Hz, 1H), 8.94 (s, 1H), 8.40(d, J = 9.2 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.89 (dd, J = 8.0, 1.6Hz, 1H), 7.48-7.43 (m, 3H), 7.03 (d, J = 7.2 Hz, 1H), 4.06-4.05 (m, 2H),3.92 (d, J = 11.6 Hz, 1H), 3.69- 3.66 (m, 1H), 3.42-3.39 (m, 1H), 3.32(d, J = 4.4 Hz, 3H), 1.86-1.83 (m, 1H), 1.69 (d, J = 12.4 Hz, 1H),1.52-1.51 (m, 3H), 1.38-1.35 (m, 1H). DMSO    95 Method G1, AQ1 427.2(M + 1) Method B (NH₄HCO₃) 1492 3HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.80(s, 1H), 9.70 (s, 1H), 9.13 (d, J = 8.0 Hz, 1H), 9.07 (s, 1H), 8.97 (d,J = 4.4 Hz, 1H), 8.94 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.32 (d, J =8.8 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.90(t, J = 6.2 Hz, 1H), 7.68 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.45 (d, J= 7.8 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 5.50 (s, 2H), 3.30 (d, J = 2.4Hz, 3H). DMSO    95 Method G1, AQ1 488.0 (M + 1) Method B (NH₄HCO₃) 14932HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 9.71 (s, 1H), 9.14 (d,J = 7.6 Hz, 1H), 8.98 (d, J = 8.0 Hz, 2H), 8.40 (d, J = 8.8 Hz, 1H),8.31 (d, J = 8.8 Hz, 1H), 7.92 (t, J = 6.2 Hz, 1H), 7.81 (t, J = 7.6 Hz,1H), 7.47-7.43 (m, 3H), 7.02 (d, J = 7.2 Hz, 1H), 4.10 (t, J = 6.0 Hz,2H), 3.53 (d, J = 6.4 Hz, 1H), 3.32 (d, J = 2.4 Hz, 3H), 2.26 (t, J =7.0 Hz, 2H), 2.00-1.93 (m, 2H), 1.73-1.63 (m, 4H), 1.55-1.51 (m, 1H),1.28-1.02 (m, 5H). DMSO    95 Method G1, AQ1 496.2 (M + 1) Method B(NH₄HCO₃) 1494 2HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 9.60 (s,1H), 8.92 (d, J = 4.4 Hz, 2H), 876 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H),8.10 (d, J = 8.0 Hz, 1H), 7.85-7.83 (m, 4H), 7.11 (d, J = 8.8 Hz, 2H),4.04 (t, J = 6.4 Hz, 2H), 3.30 (d, J = 4.0 Hz, 3H), 2.58 (d, J = 4.0 Hz,3H), 2.26 (t, J = 7.4 Hz, 2H), 2.00-1.93 (m, 2H). DMSO    95 Method G1,AQ1 428.1, 429.1, (M + 1) Method B (NH₄HCO₃) 1495 2HCl 1H-NMR (400 MHz,DMSO-d6): δ 10.63 (s, 1H), 9.73 (s, 1H), 9.17 (d, J = 7.6 Hz, 1H), 8.99(s, 1H), 8.91 (s, 1H), 8.34 (s, 2H), 7.93 (t, J = 6.0 Hz, 1H), 7.88 (d,J = 7.2 Hz, 2H), 7.09 (d, J = 7.6 Hz, 2H), 4.08-4.06 (m, 2H), 3.32 (s,3H), 2.98 (s, 3H), 2.84 (s, 3H), 2.47- 2.46 (m, 2H), 1.98-1.94 (m, 2H).DMSO    95 Method G1, AQ1 442.1, 443.1, (M + 1) Method B (NH₄HCO₃) 14962HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.64 (s, 1H), 9.01 (d,J = 7.0 Hz, 1H), 8.94 (s, 1H), 8.89 (s, 1H), 8.39 (d, J = 8.2 Hz, 1H),8.19 (d, J = 8.1 Hz, 1H), 7.85 (s, 1H), 7.47 (d, J = 5.8 Hz, 3H), 7.05(d, J = 3.4 Hz, 1H), 4.21 (dt, J = 10.8, 5.5 Hz, 1H), 4.08 (qd, J =10.1, 5.2 Hz, 2H), 3.82 (dd, J = 14.4, 7.0 Hz, 1H), 3.71 (dd, J = 14.1,7.4 Hz, 1H), 3.31 (d, J = 4.2 Hz, 3H), 2.08- 2.00 (m, 1H), 1.98-1.79 (m,2H), 1.72-1.68 (m, 1H). DMSO    95 Method G1, AQ1 413.1, 414.1, (M + 1)Method B (NH₄HCO₃) 1497 2HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H),9.68 (s, 1H), 9.09 (d, J = 7.7 Hz, 1H), 8.96 (d, J = 5.9 Hz, 2H), 8.39(d, J = 8.7 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.94-7.79 (m, 1H),7.48-7.45 (m, 3H), 7.04 (d, J = 7.5 Hz, 1H), 4.30-4.18 (m, 2H),3.80-3.70 (m, 2H), 3.44 (t, J = 6.6 Hz, 2H), 3.31 (d, J = 4.2 Hz, 3H),1.56- 1.54 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). DMSO-d₆    95 Method G1,AQ1 415.1 (M + 1) Method B (NH₄HCO₃) 1498 2HCl 1H-NMR (400 MHz,DMSO-d6): δ 10.07 (s, 1H), 9.67 (s, 1H), 9.03 (d, J = 8.0 Hz, 1H), 8.95(d, J = 4.5 Hz, 1H), 8.51 (s, 1H), 7.85 (s, 2H), 7.41 (t, J = 7.9 Hz,1H), 7.18 (dd, J = 7.8, 5.1 Hz, 2H), 7.02 (dd, J = 8.2, 2.3 Hz, 1H),3.97 (s, 3H), 3.84 (s, 3H). DMSO    95 Method G1, AQ1 373.1 (M + 1)Method B (NH₄HCO₃) 1499 2HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H),9.66 (s, 1H), 9.02 (d, J = 7.5 Hz, 1H), 8.95 (s, 1H), 8.89 (s, 1H), 8.39(d, J = 8.5 Hz, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.85 (dd, J = 7.0, 5.4Hz, 1H), 7.52-7.43 (m, 3H), 7.09-7.01 (m, 1H), 4.17-4.15 (m, 2H),3.32-3.30 (m, 4H), 3.25 (s, 3H), 1.98-1.82 (m, 2H), 1.17 (d, J = 6.1 Hz,3H). DMSO    95 Method G1, AQ1 415.1 (M + 1) Method B (NH₄HCO₃) 15002HCl 1H-NMR (400 MHz, CD3OD): δ 9.80 (s, 1H), 9.37 (d, J = 8.2 Hz, 1H),9.13 (d, J = 5.3 Hz, 1H), 8.90 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.25(dd, J = 7.9, 5.6 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.64 (s, 1H), 7.54(d, J = 5.1 Hz, 2H), 7.17 (dd, J = 7.5, 3.6 Hz, 1H), 4.70-4.62 (m, 2H),4.42 (q, J = 9.0 Hz, 2H), 3.93-3.86 (m, 2H), 3.51 (s, 3H), 3.24 (s, 3H).CD₃OD    95 Method G1, AQ1 468.1 (M + 1) Method B (NH₄HCO₃) 1501 2HCl1H-NMR (400 MHz, DMSO): δ 10.45 (brs, 1H), 9.72 (s, 1H), 9.12 (d, J =7.6 Hz, 1H), 8.97 (d, J = 4.0 Hz, 1H), 8.70 (s, 1H), 8.35 (d, J = 8.8Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.90-7.87 (m, 2H), 7.49 (d, J = 7.2Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.11 (t, J= 7.2 Hz, 1H), 4.03 (t, J = 6.4 Hz, 2H), 3.30 (d, J = 4.4 Hz, 3H), 2.54(d, J = 4.0 Hz, 3H), 2.19 (t, J = 7.4 Hz, 2H), 1.93-1.86 (m, 2H). DMSO   95 Method G1, AQ1 428.1 (M + 1) Method B (NH₄HCO₃) 1502 1H-NMR (400MHz, DMSO-d6): δ 9.65 (s, 1H). 8.88 (s, 1H), 8.81 (d, J = 8 Hz, 1H),8.73 (s, 1H), 8.62 (s, 1H), 8.19 (d, J = 8 Hz, 1H), 7.88 (d, J = 9.2 Hz,1H), 7.61- 7.58 (m, 1H), 7.47-7.44 (m, 3H), 7.06-7.04 (m, 1H), 4.56-4.54 (m, 1H), 3.87 (dd, J = 11.2, 2.0 Hz, 1H), 3.68-3.64 (m, 1H),3.56-3.53 (m, 2H), 3.21 (d, J = 4.4 Hz, 3H), 2.09-2.05 (m, 1H),1.83-1.72 (m, 2H), 1.61-1.55 (m, 1H). DMSO    95 Method G1, AQ1 413.1(M + 1) Method B (NH₄HCO₃) 1503 2HCl 1H-NMR (400 MHz, CD3OD): δ 9.77 (s,1H), 9.43 (d, J = 8.1 Hz, 1H), 9.08 (d, J = 5.6 Hz, 1H), 8.46 (s, 1H),8.34-8.25 (m, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H),7.37 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 8.3 Hz,1H), 7.00 (t, J = 7.5 Hz, 1H), 3.98 (t, J = 6.1 Hz, 2H), 3.44 (t, J =11.1 Hz, 1H), 3.35 (s, 3H), 2.17 (t, J = 7.3 Hz, 2H), 1.93-1.89 (m, 2H),1.70- 1.53 (m, 4H), 1.48 (d, J = 12.5 Hz, 1H), 1.22-1.12 (m, 2H),1.08-1.02 (m, 3H). CD₃OD    95 Method G1, AQ1 496.2 (M + 1) Method B(NH₄HCO₃) 1504 1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.76 (d, J =8.0 Hz, 1H), 8.67 (d, J = 3.6 Hz, 1H), 8.50 (d, J = 4.0 Hz, 1H), 8.10(s, 1H), 7.56-7.53 (m, 2H), 7.46- 7.42 (m, 3H), 7.03-7.01 (m, 1H), 4.07(s, 3H), 3.88 (s, 3H), 3.17 (d, J = 4.0 Hz, 1H). DMSO    95 Method G1,AQ1 372.9 (M + 1) Method B (NH₄HCO₃) 1505 1H-NMR (400 MHz, DMSO): δ 9.28(s, 1H), 8.94 (t, J = 7.6 Hz, 1H), 8.62 (d, J = 4.2 Hz, 1H), 8.42 (s,1H), 7.94 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.73-7.71 (m,1H), 7.46 (t, J = 10.0 Hz, 1H), 7.33-7.27 (m, 2H), 3.16 (d, J = 4.4 Hz,3H). DMSO    95 Method G1, AQ1 367.0 (M + 1) Method B (NH₄HCO₃) 15061H-NMR (400 MHz, DMSO): δ 8.77 (s, 1H), 8.66 (t, J = 8.6 Hz, 1H), 8.52(s, 1H), 8.44-8.31 (m, 1H), 8.03 (d, J= 8.6 Hz, 1H), 7.88 (d, J = 8.6Hz, 1H), 7.62- 7.49 (m, 3H), 7.42-7.37 (m, 1H), 3.12 (d, J = 3.0 Hz,3H). DMSO    95 Method G1, AQ1 366.9 (M + 1) Method B (NH₄HCO₃) 15071H-NMR (400 MHz, DMSO): δ 9.29 (d, J = 2.0 Hz, 1H), 8.95 (dt, J = 8.4,2.4 Hz, 1H), 8.65 (d, J = 4.4 Hz, 1H), 8.49 (s, 1H), 7.94- 7.93 (m, 2H),7.60-7.26 (m, 4H), 3.16 (d, J = 4.4 Hz, 3H). DMSO    95 Method G1, AQ1367.1 (M + 1) Method B (NH₄HCO₃) 1508 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ10.46 (s, 1H), 8.77 (s, 1H), 8.65 (t, J = 8.5 Hz, 1H), 8.55 (s, 1H),8.19 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.79 (dd, J = 15.8,7.8 Hz, 1H), 7.71-7.66 (m, 1H), 7.51 (t, J = 10.2 Hz, 1H), 7.34 (t, J =8.5 Hz, 1H), 3.23 (d, J = 3.3 Hz, 3H). DMSO    95 Method G1, AQ1 367.0(M + 1) Method B (NH₄HCO₃) 1509 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 9.98(s, 1H), 9.55 (d, J = 1.3 Hz, 1H), 9.07 (d, J = 7.2 Hz, 1H), 8.67 (s,1H), 8.16 (dd, J = 18.0. 8.4 Hz, 2H), 7.84 (d, J = 8.3 Hz, 1H), 7.78(td, J = 8.9, 6.6 Hz, 1H), 7.55-7.45 (m, 1H), 7.33 (td, J = 8.4, 2.0 Hz,1H), 3.28 (d, J = 4.4 Hz, 3H), 2.74 (s, 3H). DMSO    95 Method G1, AQ1363.1 (M + 1) Method B (NH₄HCO₃) 1510 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ10.17 (s, 1H), 8.82 (dd, J = 7.9, 6.7 Hz, 2H), 8.65 (s, 1H), 8.21 (d, J= 8.5 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.80 (s, 1H), 7.65-7.50 (m,2H), 7.42 (dd, J = 12.7, 7.6 Hz, 1H), 3.20 (d, J = 4.4 Hz, 3H), 2.94 (s,3H). DMSO    95 Method G1, AQ1 363.0 (M + 1) Method B (NH₄HCO₃) 15112HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 10.24 (s, 1H), 8.84 (d, J = 4.0 Hz,1H), 8.77 (s, 1H), 8.64 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.08 (d, J =8.6 Hz, 1H), 7.79 (td, J = 8.9, 6.6 Hz, 2H), 7.57-7.46 (m, 1H), 7.34(td, J = 8.5, 2.2 Hz, 1H), 3.20 (d, J = 4.5 Hz, 3H), 2.93 (s, 3H). DMSO   95 Method G1, AQ1 362.9 (M + 1) Method B (NH₄HCO₃) 1512 2HCl ¹H-NMR(400 MHz, DMSO-d₆): δ 9.57 (s, 1H), 8.83 (dd, J = 8.0, 1.6 Hz, 1H), 8.63(dd, J = 4.8, 2.0 Hz, 1H), 8.38 (s, 1H), 7.95-7.86 (m, 2H), 7.67-7.57(m, 2H), 7.15-7.09 (m, 2H), 4.44 (brs, 1H), 2.17 (t, J = 7.6 Hz, 1H),1.91-1.89 (m, 1H), 1.78 (d, J = 12.0 Hz, 1H), 1.56-1.48 (m, 4H),1.32-1.28 (m, 1H). DMSO    95 Method G1, AQ1 417.1 (M + 1) Method B(NH₄HCO₃) 1513 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 9.55 (s, 1H), 8.94-8.89(m, 2H), 8.58 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.8 Hz,1H), 7.85 (t, J = 6.8 Hz, 1H), 7.73 (dd, J = 14.4, 8.0 Hz, 1H),7.25-7.19 (m, 2H), 4.01 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H).DMSO    95 Method G1, AQ1 363.1 (M + 1) Method B (NH₄HCO₃) 1514 2HCl¹H-NMR (400 MHz, DMSO-d₆): δ 9.71 (s, 1H), 9.21 (d, J = 8.4 Hz, 1H),9.08 (d, J = 4.4 Hz, 1H), 8.68 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H),8.15-8.12 (m, 2H), 7.50- 7.38 (m, 3H), 4.04 (q, J = 7.2 Hz, 2H), 1.49(t, J = 7.2 Hz, 3H). DMSO    95 Method G1, AQ1 363.1 (M + 1) Method B(NH₄HCO₃) 1515 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 9.67 (s, 1H), 9.25 (d,J = 8.0 Hz, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.60 (s, 1H), 8.21-8.14 (m,2H), 8.06 (d, J = 8.4 Hz, 1H), 7.40- 7.26 (m, 3H), 4.26 (brs, 4H), 2.14(brs, 4H). DMSO-d₆    95 Method G1, AQ1 389.1 (M + 1) Method B (NH₄HCO₃)1516 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 9.60 (s, 1H), 9.14 (d, J = 8.0Hz, 1H), 9.10 (d, J = 5.2 Hz, 1H), 8.69 (s, 1H), 8.19 (d, J = 8.4 Hz,1H), 8.09 (dd, J = 8.0, 5.2 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.39-7.27(m, 3H), 4.60-4.50 (m, 1H), 2.08 (d, J = 11.6 Hz, 2H), 1.84 (d, J = 12.0Hz, 2H), 1.69 (d, J = 8.4 Hz, 1H), 1.57- 1.45 (m, 4H), 1.18-1.10 (m,1H). DMSO    95 Method G1, AQ1 417.1 (M + 1) Method B (NH₄HCO₃) 1517¹H-NMR (400 MHz, DMSO-d₆): δ 12.04 (brs, 1H), 9.58 (s, 1H), 9.38 (brs,1H), 8.84 (d, J = 5.6 Hz, 2H), 8.72 (s, 1H), 8.28 (d, J = 9.2 Hz, 1H),7.75 (t, J = 6.8 Hz, 1H), 7.51-7.41 (m, 3H), 7.07-7.03 (m, 1H), 3.88 (s,3H), 3.80 (q, J = 5.6 Hz, 2H), 2.32 (t, J = 72 Hz, 2H), 1.86-1.74 (m,2H), 1.73- 1.64 (m, 2H). DMSO    95 Method G1, AQ1 428.9 (M + 1) MethodB (NH₄HCO₃) 1518 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.61 (s, 1H), 8.74 (td, J= 8.0, 1.6 Hz, 1H), 8.71-8.66 (m, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.08(dd, J = 8.8, 2.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.87-7.81 (m, 2H),7.58-7.49 (m, 1H), 7.39- 7.30 (m, 2H), 3.49 (s, 6H). DMSO    95 MethodG1, AQ1 345.1 (M + 1) Method B (NH₄HCO₃) 1519 ¹H NMR (400 MHz, DMSO-d₆):δ 9.61 (s, 1H), 8.74 (d, J = 7.2 Hz, 1H), 8.69 (d, J = 3.6 Hz, 1H), 8.32(s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.82 (d, J= 7.6 Hz, 2H), 7.62- 7.48 (m, 3H), 3.48 (s, 6H). DMSO    95 Method G1,AQ1 361.1 363.1 (M + 1) Method B (NH₄HCO₃) 1520 ¹H-NMR (400 MHz,DMSO-d₆): δ 9.61 (s, 1H), 8.74 (td, J = 8.0, 1.6 Hz, 1H), 8.69 (dd, J =4.8, 1.6 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 8.8, 2.0 Hz,1H), 8.04-7.89 (m, 5H), 7.54 (q, J = 5.2 Hz, 1H), 3.51 (s, 6H). DMSO   95 Method G1, AQ1 352.1 (M + 1) Method B (NH₄HCO₃) 1521 ¹H-NMR (400MHz, DMSO-d₆): δ 9.61 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.68-8.60 (m,2H), 8.15 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.56 (q, J =4.8 Hz, 1H), 7.49-7.40 (m, 3H), 7.30 (s, 1H), 7.06-6.97 (m, 1H), 6.73(s, 1H), 3.87 (s, 5H), 2.14 (t, J = 7.2 Hz, 2H), 1.80-1.71 (m, 2H),1.71-1.62 (m, 2H). DMSO    95 Method G1, AQ1 428.1 (M + 1) Method B(NH₄HCO₃) 1522 2 HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 9.67 (s, 1H), 9.39 (d,J = 8.2 Hz, 1H), 9.02 (d, J = 5.3 Hz, 1H), 8.31 (d, J = 9.3 Hz, 2H),8.24- 8.10 (m, 3H), 7.88 (d, J = 7.7 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H),3.54 (s, 6H), 2.78 (s, 3H). DMSO    95 Method G1, AQ1 366.1 (M + 1)Method B (NH₄HCO₃) 1523 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.63 (d, J = 1.7Hz, 1H), 8.88- 8.32 (m, 4H), 8.16 (dd, J = 8.7, 1.8 Hz, 1H), 7.86 (t, J= 9.2 Hz, 1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H), 7.50-7.34 (m, 3H), 7.01(dt, J = 7.3, 2.1 Hz, 1H), 3.96- 3.84 (m, 5H), 2.78 (t, J = 6.9 Hz, 2H).DMSO    95 Method G1, AQ1 400.9 (M + 1) Method B (NH₄HCO₃) 1524 ¹H-NMR(400 MHz, DMSO-d₆): 9.63 (s, 1H), 8.77 (d, J = 8 Hz, 1H), 8.66-8.63 (m,3H), 8.15 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.45-7.41 (m,3H), 7.33 (s, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.79 (s, 1H), 3.88 (s, 3H),3.72 (d, J = 6.0 Hz, 2H), 2.24 (t, J = 7.2 Hz, 2H), 2.04-1.94 (m, 2H).DMSO    95 Method G1, AQ1 414.1 (M + 1) Method B (NH₄HCO₃) 1525 ¹H-NMR(400 MHz, DMSO-d₆): δ 9.58 (d, J = 1.2 Hz, 1H), 8.73- 8.68 (m, 3H), 8.37(s, 1H), 8.27- 8.22 (m, 4H), 7.89-7.87 (m, 2H), 7.75 (t, J = 8.0 Hz,1H), 7.55 (dd, J = 8.0, 5.2 Hz, 1H). DMSO    95 Method G1, AQ1 324.1(M + 1) Method B (NH₄HCO₃) 1526 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.57 (d, J= 1.6 Hz, 1H), 8.72- 8.66 (m, 2H), 8.57 (d, J = 1.6 Hz, 1H), 8.19-7.91(m, 3H), 7.83 (d, J = 8.0 Hz, 3H), 7.54 (dd, J = 7.6, 4.8 Hz, 1H), 7.10(d, J = 8.4 Hz, 2H), 3.83 (s, 3H). DMSO    95 Method G1, AQ1 329.1(M + 1) Method B (NH₄HCO₃) 1527 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.58 (s,1H), 8.72-8.66 (m, 3H), 8.16 (d, J = 8.4 Hz, 3H), 7.91 (d, J = 8.4 Hz,2H), 7.85 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.54 (dd, J =7.6, 4.3 Hz, 1H). DMSO    95 Method G1, AQ1 333.1, 335.0 (M + 1) MethodB (NH₄HCO₃) 1528 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 9.59 (s, 1H), 9.28(d, J = 8.0 Hz, 1H), 9.01 (d, J = 5.6 Hz, 2H), 8.65 (s, 2H), 8.37 (s,2H), 8.25 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 8.13 (t, J = 6.8 Hz, 1H),7.88 (d, J = 7.6 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 2.77 (s, 3H). DMSO   95 Method G1, AQ1 338.1 (M + 1) Method B (NH₄HCO₃) 1529 2HCl ¹H-NMR(400 MHz, DMSO-d₆): δ 9.78 (s, 1H), 9.72 (d, J = 1.8 Hz, 1H), 9.18 (d, J= 8.1 Hz, 1H), 8.98 (dd, J = 5.1, 1.2 Hz, 1H), 8.78 (s, 1H), 8.29 (d, J= 8.6 Hz, 1H), 8,17 (d, J = 8.6 Hz, 1H), 7.95 (dd, J = 7.9, 5.3 Hz, 1H),7.80 (td, J = 8.9, 6.6 Hz, 1H), 7.55-7.45 (m, 1H), 7.34 (td, J = 8.4,2.3 Hz, 1H), 7.26 (s, 1H), 6.96 (s, 1H), 3.98 (d, J = 6.1 Hz, 2H), 1.24(s, 6H). DMSO    95 Method G1, AQ1 434.1 (M + 1) Method B (NH₄HCO₃) 15302HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 9.58 (s, 1H), 9.04-8.89 (m, 2H),8.71-8.66 (m, 1H), 8.15- 8.11 (m, 2H), 7.82-7.76 (m, 2H), 7.51 (t, J =9.2 Hz, 1H), 7.34 (t, J = 8.8 Hz, 1H), 4.64 (s, 2H), 3.19 (s, 3H), 2.91(s, 3H). DMSO    95 Method G1, AQ1 420.1 (M + 1) Method B (NH₄HCO₃) 1531¹H-NMR (400 MHz, DMSO-d₆): δ 9.63 (s, 1H), 8.78 (d, J = 7.9 Hz, 1H),8.72 (d, J = 3.2 Hz, 1H), 8.19 (s, 2H), 8.08-7.97 (m, 2H), 7.80 (dd, J =15.5, 8.9 Hz, 1H), 7.58 (dd, J = 7.6, 4.9 Hz, 1H), 7.52-7.41 (m, 1H),7.29 (td, J = 8.3, 1.9 Hz, 1H), 4.48 (s, 2H), 4.15 (s, 2H), 3.48 (s,2H). DMSO    95 Method G1, AQ1 418.1 (M + 1) Method B (NH₄HCO₃) 1532¹H-NMR (400 MHz, DMSO-d₆): δ 9.65 (s, 1H), 8.87 (s, 1H), 8.79 (d, J =7.7 Hz, 1H), 8.70 (s, 1H), 8.59 (s, 1H), 8.23 (s, 1H), 8.05- 7.89 (m,3H), 7.75 (dd, J = 15.1, 7.6 Hz, 1H), 7.56 (s, 1H), 7.48 (t, J = 9.9 Hz,1H), 7.32 (t, J = 8.1 Hz, 1H), 4.46 (t, J = 13.4 Hz, 2H). DMSO    95Method G1, AQ1 442.0 (M + 1) Method B (NH₄HCO₃) 1533 2HCl ¹H-NMR (400MHz, DMSO-d₆): δ 9.63 (s, 1H), 8.95-9.03 (m, 2H), 8.78 (s, 1H),8.14-8.24 (m, 2H), 7.88 (t, J = 6.0 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H),7.54-7.48 (m, 1H), 7.35-7.32 (m, 1H), 4.89 (m, 1H), 1.39 (d, J = 1.2 Hz,6H). DMSO    95 Method G1, AQ1 377.1 (M + 1) Method B (NH₄HCO₃) 15342HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 9.61 (s, 1H), 8.69-8.74 (m, 2H), 8.59(s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.71-7.77(m, 1H), 7.66 (s, 1H), 7.56-7.60 (m, 1H), 7.42-7.48 (m, 1H), 7.27-7.32(m, 1H), 1.66 (s, 9H). DMSO    95 Method G1, AQ1 391.1 (M + 1) Method B(NH₄HCO₃) 1535 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 9.74 (s, 1H), 9.66 (s,1H), 9.22 (d, J = 7.6 Hz, 1H), 8.99 (d, J = 4.8 Hz, 1H), 8.83 (s, 1H),8.33 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.95 (t, J = 6.2 Hz,1H), 7.58 (q, J = 8.6 Hz, 1H), 7.51 (t, J = 7.0 Hz, 1H), 7.46-7.41 (m,1H), 7.25 (s, 1H), 6.72 (s, 1H), 5.13-5.06 (m, 1H), 3.21 (q, J = 7.3 Hz,1H), 2.22-1.92 (m, 5H), 1.68-1.57 (m, 1H). DMSO    95 Method G1, AQ1446.0 (M + 1) Method B (NH₄HCO₃) 1536 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ9.81 (s, 2H), 9.32 (d, J = 8.0 Hz, 1H), 9.02 (d, J = 5.2 Hz, 1H), 8.81(s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.00 (dd, J= 7.8, 5.8 Hz, 1H), 7.76 (dd, J = 15.4, 3.6 Hz, 1H), 7.51 (t, J = 10.0Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.29 (s, 1H), 6.73 (s, 1H), 5.15-5.07(m, 1H), 3.21 (q, J = 7.3 Hz, 1H), 2.23- 1.87 (m, 5H), 1.68-1.57 (m,1H). DMSO    95 Method G1, AQ1 446.1 (M + 1) Method B (NH₄HCO₃) 1537¹H-NMR (400 MHz, DMSO-d₆): δ 9.66 (s, 1H), 8.79 (d, J = 7.6 Hz, 1H),8.69 (dd, J = 4.4, 1.2 Hz, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.40 (d, J =7.2 Hz, 1H), 8.13 (dd, J = 8.6, 1.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H),7.55 (dd, J = 7.6, 4.8 Hz, 1H), 7.49-7.40 (m, 3H), 7.11 (s, 1H), 7.02(d, J = 7.2 Hz, 1H), 6.69 (s, 1H), 5.03-4.96 (m, 1H), 3.87 (s, 3H), 3.20(dd, J = 15.0, 7.4 Hz, 1H), 2.22-1.88 (m, 5H), 1.70-1.56 (m, 1H). DMSO   95 Method G1, AQ1 Method B (NH₄HCO₃) 1538 ¹H-NMR (400 MHz, DMSO-d₆):δ 9.60 (s, 1H), 8.86 (d, J = 7.7 Hz, 1H), 8.74 (d, J = 8.0 Hz, 1H), 8.69(d, J = 3.3 Hz, 1H), 8.65 (s, 1H), 8.19 (d, J = 7.4 Hz, 1H), 7.87 (d, J= 8.8 Hz, 2H), 7.54 (dd, J = 7.8, 4.8 Hz, 1H), 7.50- 7.40 (m, 3H), 7.01(dd, J = 7.3, 3.9 Hz, 1H), 4.85 (dd, J = 16.9, 8.7 Hz, 1H), 3.88 (s,3H), 2.16 (s, 2H), 1.96 (s, 2H). DMSO    95 Method G1, AQ1 426.1, 427.1(M + 1) Method B (NH₄HCO₃) 1539 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 10.34(s, 1H), 9.67 (s, 1H), 9.07 (s, 1H), 8.97 (d, J = 5.0 Hz, 1H), 8.92 (s,1H), 8.39 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 7.4 Hz, 1H), 7.99 (s, 1H),7.90 (s, 1H), 7.48 (d, J = 5.8 Hz, 3H), 7.09-6.99 (m, 1H), 4.03 (d, J =6.1 Hz, 2H), 3.89 (s, 3H), 2.65 (t, J = 6.8 Hz, 2H), 2.56 (d, J = 4.4Hz, 3H). DMSO    95 Method G1, AQ1 414.0, 415.0 (M + 1) Method B(NH₄HCO₃) 1540 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 10.48 (s, 1H), 9.64 (s,1H), 9.05 (d, J = 7.9 Hz, 1H), 9.01-8.92 (m, 2H), 8.38 (d, J = 8.8 Hz,1H), 8.28 (d, J = 8.6 Hz, 1H), 7.93- 7.83 (m, 1H), 7.55-7.43 (m, 3H),7.08-6.98 (m, 1H), 4.04 (dd, J = 12.4, 6.6 Hz, 2H), 3.89 (s, 3H), 2.98(s, 3H), 2.89 (t, J = 7.0 Hz, 2H), 2.34 (s, 3H). DMSO    95 Method G1,AQ1 428.1, 429.1 (M + 1) Method B (NH₄HCO₃) 1541 2HCl ¹H-NMR (400 MHz,DMSO-d₆): δ 10.02 (brs, 1H), 9.75 (d, J = 1.6 Hz, 1H), 9.07 (dd, J =8.0, 1.6 Hz, 1H), 8.83 (s, 1H), 8.35 (d, J = 9.2 Hz, 1H), 8.19 (d, J =8.6 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.48-7.46 (m, 3H), 7.06-7.03 (m,1H), 3.89 (s, 3H), 3.30 (d, J = 4.0 Hz, 3H). DMSO    95 Method G1, AQ1411.1 (M + 1) Method B (NH₄HCO₃) 1542 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ10.22 (brs, 1H), 9.64 (s, 1H), 9.01 (d, J = 6.4 Hz, 1H), 8.95 (d, J =4.0 Hz, 1H), 8.89 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.0Hz, 1H), 7.85 (t, J = 5.2 Hz, 1H), 7.52-7.42 (m, 4H), 7.08-7.05 (m, 1H),6.89 (s, 1H), 3.89 (s, 4H), 3.83-3.76 (m, 2H), 2.83- 2.79 (m, 1H),1.65-1.56 (m, 7H), 1.24-1.07 (m, 6H), 0.89- 0.81 (m, 2H). DMSO    95Method G1, AQ1 510.2 (M + 1) Method B (NH₄HCO₃) 1543 ¹H-NMR (400 MHz,DMSO-d₆): δ 9.67 (d, J = 1.6 Hz, 1H), 8.80 (dt, J = 8.0, 2.0 Hz, 1H),8.70 (dd, J = 4.4, 2.0 Hz, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.71-7.67(m, 1H), 7.58-7.55 (m, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.34 (m, 2H), 3.45(s, 6H), 2.76 (s, 3H). DMSO    95 Method G1, AQ1 359.1 (M + 1) Method B(NH₄HCO₃) 1544 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.66 (s, 1H), 8.82-8.79 (m,1H), 8.70 (d, J = 4.0 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.02 (s, 1H),7.86-7.84 (m, 2H), 7.58-7.55 (m, 3H), 3.48 (s, 6H), 2.77 (s, 3H). DMSO   95 Method G1, AQ1 375.1 (M + 1) Method B (NH₄HCO₃) 1545 ¹H-NMR (400MHz, DMSO-d₆): δ 9.68 (s, 1H), 9.01 (d, J = 8.0 Hz, 1H), 8.82 (d, J =4.4 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.03 (s, 1H), 7.88-7.84 (m, 2H),7.80- 7.77 (m, 1H), 7.37-7.33 (m, 2H), 3.50 (s, 6H), 2.78 (s, 3H). DMSO   95 Method G1, AQ1 359.1 (M + 1) Method B (NH₄HCO₃) 1546 ¹H-NMR (400MHz, CD₃OD): δ 9.51 (s, 1H), 8.81 (d, J = 7.3 Hz, 1H), 8.54 (s, 1H),8.35 (s, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.50(d, J = 7.2 Hz, 1H), 7.29 (dt, J = 11.2, 4.8 Hz, 3H), 6.88 (d, J = 7.5Hz, 1H), 4.43 (dd, J = 7.1, 4.0 Hz, 1H), 4.16 (dd, J = 13.8, 4.0 Hz,1H), 3.86 (dd, J = 13.7, 7.4 Hz, 1H), 3.80 (s, 3H). CD3OD    95 MethodG1, AQ1 416.1 (M + 1) Method B (NH₄HCO₃) 1547 2HCl ¹H-NMR (400 MHz,CD₃OD): δ 9.74 (s, 1H), 9.44 (d, J = 8.2 Hz, 1H), 9.02 (d, J = 5.5 Hz,1H), 8.50 (s, 1H), 8.24 (dd, J = 8.0, 5.9 Hz, 1H), 8.16 (q, J = 8.7 Hz,2H), 7.70-7.58 (m, 1H), 7.12- 7.00 (m, 2H), 6.13 (s, 1H), 4.44- 4.41 (m,1H), 4.29-4.27 (m, 1H), 2.37-2.16 (m, 3H), 2.09- 2.07 (m, 1H). CD₃OD   95 Method G1, AQ1 457.0 (M + 1) Method B (NH₄HCO₃) 1548 2HCl ¹H-NMR(400 MHz, CD₃OD): δ 9.85 (s, 1H), 9.57 (d, J = 8.0 Hz, 1H), 9.10 (d, J =4.8 Hz, 1H), 8.64 (s, 1H), 8.34-8.22 (m, 3H), 7.51 (t, J = 6.9 Hz, 1H),7.47- 7.33 (m, 2H), 6.23 (s, 1H), 4.53- 4.51 (m, 1H), 4.38-4.36 (m, 1H),2.51-2.30 (m, 3H), 2.19- 2.18 (m, 1H). CD₃OD    95 Method G1, AQ1 457.1(M + 1) Method B (NH₄HCO₃) 1549 2HCl ¹H-NMR (400 MHz, DMSO): δ 10.38(brs, 1H), 9.63 (d, J = 1.6 Hz, 1H), 9.00 (d, J = 8.0 Hz, 1H), 8.95-8.94(m, 2H), 8.39 (d, J = 9.2 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1 H), 7.88-7.85(m, 1 H), 7.49- 7.48 (m, 3H), 7.07-7.04 (m, 1H), 3.94-3.89 (m, 5H),3.60- 3.57 (m, 2H), 1.96-1.93 (m, 2H). DMSO    95 Method G1, AQ1 387.1(M + 1) Method B (NH₄HCO₃) 1550 ¹H-NMR (400 MHz, DMSO): δ 9.62 (s, 1H),8.72-8.70 (m, 2H), 8.40 (s, 1H), 8.11-7.94 (m, 2H), 7.91-7.74 (m, 3H),7.54 (dd, J = 7.6, 4.8 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 3.83 (s, 3H),2.74 (s, 3H). DMSO    95 Method G1, AQ1 343.1 (M + 1) Method B (NH₄HCO₃)1551 ¹H-NMR (400 MHz, DMSO): δ 9.64 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H),8.70 (d, J = 4.4 Hz, 1H), 8.46 (s, 1H), 8.12-7.83 (m, 5H), 7.57 (dd, J =7.8, 4.8 Hz, 1H), 7.39 (t, J = 8.7 Hz, 2H), 2.84 (s, 3H). DMSO    95Method G1, AQ1 331.1 (M + 1) Method B (NH₄HCO₃) 1552 1H-NMR (400 MHz,DMSO): δ 9.62 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H), 8.71 (d, J = 4.4 Hz,1H), 8.23 (s, 1H), 8.20 (s, 1H), 8.07- 8.00 (m, 2H), 7.60-7.50 (m, 3H),7.40-7.37 (m, 1H), 4.48 (s, 2H), 4.12-4.10 (m, 2H), 3.48- 3.46 (m, 2H).DMSO    95 Method G1, AQ1 418.1 (M + 1) Method B (NH₄HCO₃) 1553 2HCl¹H-NMR (400 MHz, DMSO-d₆): δ 9.74 (s, 1H), 9.45 (s, 1H), 9.27 (d, J =8.8 Hz, 1H), 8.97 (s, 1H), 8.69 (s, 1H), 8.12-8.00 (m, 3H), 7.83-7.76(m, 1H), 7.51-7.32 (m, 2H), 480-4.64 (m, 2H). DMSO    95 Method G1, AQ1417.1 (M + 1) Method B (NH₄HCO₃) 1554 2HCl ¹H-NMR (400 MHz, CD3OD): δ9.86 (s, 1H), 9.48 (d, J = 8.8 Hz, 1H), 9.18 (d, J = 5.2 Hz, 1H), 8.72(s1H), 8.92 (s, 1H), 8.37- 8.31 (m, 2H), 8.22 (d, J = 8.8 Hz, 1H),7.80-7.55 (m, 1H), 7.26- 7.20 (m, 2H), 4.92 (d, J = 4.8 Hz, 1H), 4.81(t, J = 4.8 Hz, 1H), 4.39-4.30 (m, 2H). CD3OD    95 Method G1, AQ1 380.9(M + 1) Method B (NH₄HCO₃) 1555 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.62 (s,1H), 8.7-8.68 (m, 2H), 8.32 (s, 1H), 7.97-7.93 (m, 2H), 7.91-7.36 (m,5H), 347 (s, 6H). DMSO    95 Method G1, AQ1 345.1 (M + 1) Method B(NH₄HCO₃) 1556 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.61 (s, 1H), 8.75 (d, J =8.0 Hz, 1H), 8.67 (d, J = 3.6 Hz, 2H), 8.48 (s, 1H), 8.13 (d, J = 8.8Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.59-7.49 (m, 3H), 7.45-7.30 (m, 5H),7.02-6.92 (m, 1H), 4.50 (q, J = 3.2 Hz, 1H), 4.39- 4.20 (m, 2H),4.14-4.09 (m, 1H), 3.98-3.83 (m, 1H), 3.38 (s, 3H), 2.49-2.40 (m, 1H),2.35- 2.18 (m, 1H). DMSO    95 Method G1, AQ1 493.0 495.0 (M + 1) MethodB (NH₄HCO₃) 1557 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.60 (s, 1H), 8.73 (dd, J= 7.6, 1.2 Hz, 1H), 8.67 (dd, J = 8.4, 1.2 Hz, 1H), 8.47 (s, 1H), 8.11(dd, J = 8.4, 1.6 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.54-7.50 (m, 1H),7.42 (t, J = 8.0 Hz, 1H), 7.38- 7.32 (m, 2H), 7.32-7.23 (m, 2H), 7.05(d, J = 8.4 Hz, 1H), 7.00-6.92 (m, 2H), 4.45 (t, J = 8.4 Hz, 1H), 4.24(s, 2H), 4.08- 3.95 (m, 1H), 3.88-3.80 (m, 7H), 2.44-2.33 (m, 1H), 2.29-2.15 (m, 1H). DMSO    95 Method G1, AQ1 489.1 (M + 1) Method B (NH₄HCO₃)1558 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.56 (s, 1H), 9.02 (s, 1H), 8.19 (d, J= 7.5 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.58 (dd, J = 7.7, 4.9 Hz, 1H),7.52-7.37 (m, 3H), 7.37-7.24 (m, 3H), 7.12 (t, J = 8.8 Hz, 2H), 7.02 (d,J = 7.5 Hz, 1H), 6.84 (s, 1H), 3.89-3.78 (m, 4H), 3.72-3.66 (m, 1H),3.13 (s, 1H), 2.97-2.90 (m, 1H), 2.86- 2.78 (m, 1H). DMSO    95 MethodG1, AQ1 506.1 (M + 1) Method B (NH₄HCO₃) 1559 2 HCl ¹H-NMR (400 MHz,DMSO-d₆): δ 10.48-10.00 (m, 1H), 9.70 (s, 1H), 9.12-8.77 (m, 3H), 8.42-8.32 (m, 1H), 8.30-8.17 (m, 1H), 7.95-7.79 (m, 1H), 7.55- 7.44 (m, 6H),7.26 (d, J = 7.2 Hz, 1H), 7.05 (s, 1H), 6.94 (S, 1H), 3.89 (s, 5H), 3.22(s, 1H), 2.97- 2.81 (m, 2H). DMSO    95 Method G1, AQ1 558.1 560.0 562.0(M + 1) Method B (NH₄HCO₃) 1560 2 HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 10.25(s, 1H), 9.61 (d, J = 1.5 Hz, 1H), 8.96 (d, J = 4.0 Hz, 1H), 8.87 (s,1H), 8.39 (d, J = 8.5 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H), 7.87 (s, 1H),7.52-7.44 (m, 4H), 7.36 (t, J = 7.6 Hz, 1H), 7.28 (dd, J = 13.5, 6.0 Hz,1H), 7.22-7.10 (m, 2H), 7.06 (d, J = 7.5 Hz, 1H), 6.89 (s, 1H),3.95-3.81 (m, 5H), 3.21 (d, J = 9.0 Hz, 1H), 2.94 (d, J = 7.3 Hz, 2H).DMSO    95 Method G1, AQ1 508.2 (M + 1) Method B (NH₄HCO₃) 1561 ¹H-NMR(400 MHz, DMSO-d₆): δ 9.64 (s, 1H), 8.71 (m, 2H), 8.69 (d, J = 3.5 Hz,1H), 8.64 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H),7.58-7.49 (m, 1H), 7.43 (m, 4H), 7.28-7.18 (m, 4H), 7.15 (m, 1H), 7.01(d, J = 7.2 Hz, 1H), 6.94 (s, 1H), 3.82- 3.73 (m, 5H), 2.90-2.87 (m.1H), 2.68-2.65 (m, 2H), 1.89- 1.86 (m, 2H). DMSO    95 Method G1, AQ1503.9 (M + 1) Method B (NH₄HCO₃) 1562 ¹H-NMR (400 MHz, DMSO-d₆): 9.85(s, 1H), 8.76 (s, 1H), 8.65 (d, J = 3.6 Hz, 1H), 8.64 (s, 1H), 8.53 (d,J = 8.0 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H),7.51 (dd, J = 8.0, 4.7 Hz, 1H), 7.45 (d, J = 6.7 Hz, 2H), 7.40 (s, 1H),7.31-7.27 (m, 5H), 7.24 (d, J = 6.6 Hz, 1H), 7.00 (d, J = 6.9 Hz, 1H),6.80 (s, 1H), 3.77-3.70 (m, 5H), 3.17-3.15 (m, 1H), 2.98-2.81 (m, 2H).DMSO    95 Method G1, AQ1 489.9 (M + 1) Method B (NH₄HCO₃) 1563 ¹H-NMR(400 MHz, DMSO-d₆): δ 9.57 (s, 1H), 8.74-8.68 (m, 2H), 8.21 (s, 1H),8.15 (dd, J = 8.7, 1.6 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.56-7.52 (m,2H), 7.46- 7.31 (m, 4H), 7.12 (d, J = 6.5 Hz, 2H), 6.95-6.93 (m, 1H),5.16 (s, 2H), 3.78 (s, 3H), 3.53 (s, 3H). DMSO    95 Method G1, AQ1467.1, 469.1 (M + 1) Method B (NH₄HCO₃) 1564 ¹H-NMR (400 MHz, DMSO-d₆):δ 9.64 (d, J = 1.4 Hz, 1H), 8.75 (d, J = 7.9 Hz, 1H), 8.70 (d, J = 4.6Hz, 1H), 8.32 (s, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.7 Hz,1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.36-7.29 (m, 2H), 7.01-6.98 (m, 1H), 6.88 (s, 1H), 6.83 (s, 2H), 4.12-4.03(m, 2H), 3.85 (s, 3H), 3.69 (s, 3H), 3.62 (s, 3H), 3.56 (d, J = 8.0 Hz,3H), 3.15-3.02 (m, 2H). DMSO    95 Method G1, AQ1 507.2 (M + 1) Method B(NH₄HCO₃) 1565 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.64 (d, J = 2.0 Hz, 1H),8.77- 8.69 (m, 2H), 8.68 (d, J = 1.6 Hz, 1H), 8.64 (d, J = 1.6 Hz, 1H),8.16 (dd, J = 3.8, 1.6 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.55- 7.52 (m,1H ), 7.46-7.41 (m, 4H), 7.29 (t, J = 7.2 Hz, 1H), 7.23- 7.19 (m, 1H),7.14-7.06 (m, 2H), 7.01 (dt, J = 9.2 , 2.0 Hz, 1H), 6.96 (s, 1H),3.87-3.76 (m, 5H), 2.94-2.93 (m, 1H), 2.68 (t, J = 7.8 Hz, 2H), 1.89-1.83 (m, 2H). DMSO    95 Method G1, AQ1 522.3 (M + 1) Method B (NH₄HCO₃)1566 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.59 (s, 1H), 8.76 (t, J = 5.2 Hz,1H), 8.69 (dd, J = 4.4, 1.2 Hz, 1H), 8.63 (s, 1H), 8.56 (d, J = 8.4 Hz,1H), 8.15 (dd, J = 8.8, 1.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.53-7.50(m, 1H), 7.48-7.40 (m, 3H), 7.36-7.32 (m, 3H), 7.30-7.24 (m, 2H),7.02-7.00 (m, 1H), 6.85 (s, 1H), 3.92-3.83 (m, 4H), 3.72-3.69 (m, 1H),3.18-3.14 (m, 1H), 2.96-2.84 (m, 2H). DMSO    95 Method G1, AQ1 524.2,526.2 (M + 1) Method B (NH₄HCO₃) 1567 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.64(s, 1H), 9.08 (s, 1H), 8.79- 8.69 (m, 2H), 8.51 (s, 1H), 8.31 (s, 1H),8.00-7.89 (m, 2H), 7.85- 7.69 (m, 1H), 7.67-7.42 (m, 2H), 7.30-7.21 (m,2H), 5.00 (d, J = 5.1 Hz, 2H). DMSO    95 Method G1, AQ1 416.0 (M + 1)Method B (NH₄HCO₃) 1568 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 10.58 (s, 1H),10.09 (d, J = 4.4 Hz, 1H), 9.65 (s, 1H), 9.05-9.02 (m, 2H), 8.95 (d, J =4.4 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.30- 8.27 (m, 1H), 7.85 (t, J =6.2 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.49-7.43 (m, 3H), 7.24 (t, J =7.8 Hz, 2H), 7.03-6.97 (m, 2H), 3.89 (s, 3H), 3.86-3.84 (m, 2H), 2.44(t, J = 7.0 Hz, 2H), 1.87- 1.77 (m, 4H). DMSO    95 Method G1, AQ1 504.1(M + 1) Method B (NH₄HCO₃) 1569 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 10.62(s, 1H), 9.67 (s, 1H), 9.08 (d, J = 7.2 Hz, 1H), 9.03 (s, 1H), 8.97 (d,J = 5.2 Hz, 1H), 8.44 (t, J = 5.6 Hz, 1H), 8.40 (dd, J = 8.8, 0.8 Hz,1H), 8.32 (dd, J = 9.2, 2.8 Hz, 1H), 7.89 (t, J = 6.4 Hz, 1H), 7.50-7.44(m, 3H), 7.25-7.14 (m, 5H), 7.03 (d, J = 7.2 Hz, 1H), 4.24 (d, J = 6.0Hz , 2H), 3.89 (s, 3H), 3.87-3.82 (m, 2H), 2.26 (t, J = 7.0 Hz, 2H),1.84-1.69 (m, 4H). DMSO    95 Method G1, AQ1 518.1 (M + 1) Method B(NH₄HCO₃) 1570 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.55 (s, 1H), 8.69 (dd, J =11.3, 6.2 Hz, 2H), 8.23 (s, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.95 (d, J =8.7 Hz, 1H), 7.59-7.50 (m, 2H), 7.44-7.26 (m, 3H), 7.23 (t, J = 7.5 Hz,1H), 7.15 (s, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H),5.18 (s, 2H), 3.79 (s, 3H), 3.54 (s, 3H). DMSO    95 Method G1, AQ1451.2, 452.2, 453.2 (M + 1) Method B (NH₄HCO₃) 1571 2HCl ¹H-NMR (400MHz, DMSO-d₆): δ 9.62 (s, 1H), 9.60 (s, 1H), 8.88 (d, J = 4.3 Hz, 1H),8.82 (s, 1H), 8.78 (d, J = 8.1 Hz, 1H), 8.31 (d, J = 8.6 Hz, 1H), 8.12(d, J = 7.9 Hz, 1H), 7.75 (dd, J = 7.8, 5.l Hz, 1H), 7.53-7.39 (m, 4H),7.33 (dd, J = 14.3, 7.9 Hz, 1H), 7.12 (t, J = 7.8 Hz, 2H), 7.03 (dd, J =11.0, 6.3 Hz, 2H), 6.90 (s, 1H), 3.97-3.90 (m, 4H), 3.82 (dd, J = 18.0,9.5 Hz, 1H), 3.19 (dd, J = 13.4, 7.5 Hz, 1H), 2.98 (dd, J = 13.6, 7.9Hz, 1H), 2.87 (dd, J = 13.6, 6.7 Hz, 1H). DMSO    95 Method G1, AQ1508.1, 509.1, 510.1 (M + 1) Method B (NH₄HCO₃) 1572 2HCl ¹H-NMR (400MHz, DMSO-d₆): δ 10.20 (s, 1H), 9.61 (s, 1H), 8.94 (d, J = 4.8 Hz, 1H),8.86 (s, 2H), 8.37 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 7.83 (s, 1H),7.56-7.32 (m, 6H), 7.31-7.19 (m, 2H), 7.06 (d, J = 7.2 Hz, 1H), 6.89 (s,1H), 4.03-3.93 (m, 1H), 3.88 (s, 3H), 3.82 (dd, J = 14.4, 5.5 Hz, 1H),3.22 (s, 1H), 3.02 (d, J = 7.2 Hz, 2H). DMSO    95 Method G1, AQ1 524.1,525.1, 526.0 (M + 1) Method B (NH₄HCO₃) 1573 2HCl ¹H-NMR (400 MHz,DMSO-d₆): δ 10.31 (s, 1H), 9.63 (s, 1H), 8.96 (d, J = 4.4 Hz, 1H), 8.90(s, 1H), 8.84 (d, J = 7.7 Hz, 1H), 8.39 (d, J = 8.7 Hz, 1H), 8.27 (d, J= 8.0 Hz, 1H), 7.91-7.80 (m, 1H), 7.48 (dd, J = 15.6, 7.7 Hz, 3H), 7.36(s, 1H), 7.24-7.03 (m, 5H), 6.85 (s, 1H), 4.03-3.93 (m, 1H), 3.88 (s,3H), 3.83 (dd, J = 14.7, 7.6 Hz, 1H), 3.15 (s, 1H), 2.94 (dd, J = 13.8,8.0 Hz, 1H), 2.84 (dd, J = 13.8, 6.6 Hz, 1H), 2.29 (s, 3H). DMSO    95Method G1, AQ1 504.1, 505.2, 506.1 (M + 1) Method B (NH₄HCO₃) 1574 2HCl¹H-NMR (400 MHz, DMSO-d₆): δ 10.43 (s, 1H), 9.71 (s, 1H), 9.05 (d, J =4.7 Hz, 1H), 9.01 (d, J = 7.6 Hz, 1H), 8.96 (s, 1H), 8.45 (d, J = 8.6Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.99-7.89 (m, 1H), 7.61-7.41 (m, 4H),7.23 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.6 Hz, 3H), 6.93 (s, 1H),4.01-3.84 (m, 5H), 3.31-3.21 (m, 1H), 3.02- 2.97 (m, 7.5 Hz, 1H),2.87-2.81 (m, 1H), 2.29 (s, 3H). DMSO    95 Method G1, AQ1 504.1 (M + 1)Method B (NH₄HCO₃) 1575 ¹H-NMR (400 MHz, CD₃OD): δ 9.39 (s, 1H), 8.69(d, J = 8.0 Hz, 1H), 8.65 (s, 1H), 8.38 (s, 1H), 8.07 (d, J = 7.9 Hz,1H), 7.85 (d, J = 8.6 Hz, 1H), 7.60-7.53 (m, 1H), 7.35-7.25 (m, 5H),7.18 (dd, J = 13.6, 7.2 Hz, 2H), 7.12 (s, 1H), 6.88 (dd, J = 7.9, 2.1Hz, 1H), 4.49 (dd, J = 11.3, 7.9 Hz, 1H), 4.36-4.17 (m, 2H), 4.04 (t, J= 10.4 Hz, 1H), 3.74 (s, 3H), 3.60-3.49 (m, 1H), 2.50-2.39 (m, 1H),2.27-2.14 (m, 1H). CD3OD    95 Method G1, AQ1 459.0 (M + 1) Method B(NH₄HCO₃) 1576 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.67 (d, J = 1.7 Hz, 1H),9.05 (s, 1H), 8.94 (d, J = 3.7 Hz, 1H), 8.59 (s, 1H), 8.40-8.22 (m, 2H),7.85 (s, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H),7.52-7.36 (m, 4H), 7.04 (d, J = 7.6 Hz, 1H), 4.74-4.72 (m, 2H),4.48-4.43 (m, 3H), 3.85 (s, 3H), 3.74-3.60 (m, 1H), 2.25-2.23 (m, 1H).DMSO    95 Method G1, AQ1 527.0, 529.0 (M + 1) Method B (NH₄HCO₃) 15772HCl ¹H-NMR (400 MHz, DMSO): δ 9.69 (d, J = 1.6 Hz, 1H), 8.89 (d, J =8.0 Hz, 1H), 8.79 (d, J = 1.6 Hz, 1H), 8.73 (s, 1H), 8.21 (d, J = 9.2Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.67 (dd, J = 7.6, 4.8 Hz, 1H),7.56-7.38 (m, 7H), 7.05-7.02 (m, 1H), 5.59 (s, 4H), 3.89 (s, 3H). DMSO   95 Method G1, AQ1 431.1 (M + 1) Method B (NH₄HCO₃) 1578 ¹H-NMR (400MHz, DMSO): δ 9.59 (d, J = 1.6 Hz, 1H), 8.81-8.64 (m, 2H), 8.28-8.10 (m,2H), 7.96 (d, J = 8.6 Hz, 1H), 7.55 (td, J = 8.5, 5.0 Hz, 3H), 7.40-7.06(m, 5H), 6.94 (dd, J = 8.2, 2.0 Hz, 1H), 5.15 (s, 2H), 3.78 (s, 3H),3.51 (s, 3H). DMSO    95 Method G1, AQ1 451.2 (M + 1) Method B (NH₄HCO₃)1579 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 10.61 (s, 1H), 9.66 (s, 1H), 9.00(d, J = 13.5 Hz, 3H), 8.43-8.31 (m, 2H), 7.89 (s, 1H), 7.48 (dd, J =14.6, 7.2 Hz, 3H), 7.33-7.22 (m, 4H), 7.21-7.14 (m, 1H), 7.05 (d, J =7.2 Hz, 1H), 4.10- 3.85 (m, 2H), 3.90 (s, 3H), 3.37- 3.27 (m, 1H),3.07-2.91 (m, 2H). DMSO    95 Method G1, AQ1 491.2 (M + 1) Method B(NH₄HCO₃) 1580 2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 9.91 (s, 1H), 9.60 (s,1H), 9.11 (s, 1H), 9.95 (s, 1H), 8.66 (s, 1H), 8.20-8.02 (m, 3H), 7.97(s, 1H), 7.78 (dd, J = 13.3, 6.5 Hz, 1H), 7.50 (t, J = 11.3 Hz, 1H),7.33 (t, J = 8.1 Hz, 1H), 7.21 (s, 1H), 5.08 (d, J = 3.8 Hz, 2H). DMSO   95 Method G1, AQ1 416.0 (M + 1) Method B (NH₄HCO₃) 1581 2HCl ¹H-NMR(400 MHz, DMSO-d₆): δ 9.84 (s, 1H), 9.71 (s, 1H), 9.12 (d, J = 6.2 Hz,1H), 8.96 (d, J = 4.8 Hz, 1H), 8.91 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H),8.30 (s, 1H), 7.88 (s, 1H), 7.57-7.38 (m, 3H), 7.24 (s, 1H), 7.08 (d, J= 7.9 Hz, 1H), 6.73 (s, 1H), 5.18-5.05 (m, 1H), 3.88 (s, 3H), 3.23 (dd,J = 14.8, 7.4 Hz, 1H), 2.31-2.17 (m, 1H), 2.15-1.89 (m, 4H), 1.71- 1.57(m, 1H). DMSO    95 Method G1, AQ1 440.2 (M + 1) Method B (NH₄HCO₃) 15832HCl 1H-NMR (300 MHz, DMSO): δ 10.39 (s, 1H), 9.71 (s, 1H), 9.14 (d, J =8.1 Hz, 1H), 8.98 (d, J = 4.0 Hz, 1H), 8.71 (s, 1H), 8.31 (d, J = 8.8Hz, 1H), 8.25-8.19 (m, 1H), 7.96-7.89 (m, 1H), 7.38 (dd, J = 9.2, 3.0Hz, 1H), 7.34- 7.14 (m, 2H), 3.81 (s, 4H), 3.30 (d, J = 4.4 Hz, 4H).DMSO    95 Method AQ2, AP 361.7 (M + 1) Method C 1584 2HCl 1H-NMR (300MHz, DMSO): δ 10.84 (s, 1H), 9.01 (s, 1H), 8.95 (d, J = 3.9 Hz, 1H),8.72 (d, J = 7.8 Hz, 1H), 8.50-8.40 (m, 1H), 8.33 (d, J = 8.8 Hz, 1H),8.24 (td, J = 7.8, 1.7 Hz, 1H), 7.85 (dd, J = 6.5, 4.8 Hz, 1H),7.57-7.43 (m, 3H), 7.09-7.02 (m, 1H), 3.90 (s, 3H), 3.38 (s, 3H) DMSO   95 Method AQ2, AP 343.5 (M + 1) Method C 1585 2HCl 1H-NMR (300 MHz,DMSO): δ 10.44-10.13 (m, 1H), 9.66 (s, 1H), 9.08 (d, J = 10.1 Hz, 2H),8.96 (d, J = 3.7 Hz, 1H), 8.44 (d, J = 8.9 Hz, 1H), 8.22 (d, J = 8.4 Hz,1H), 8.13 (dd, J = 13.3, 5.3 Hz, 2H), 8.00 (d, J = 8.2 Hz, 1H), 7.91 (s,1H), 3.30 (d, J = 4.4 Hz, 3H). DMSO    95 Method AQ2, AP 356.4 (M + 1)Method C 1586 1H-NMR (300 MHz, DMSO): δ 9.64 (s, 1H), 8.78 (d, J = 8.0Hz, 1H), 8.73-8.69 (m, 1H), 8.63 (s, 2H), 8.47-8.37 (m, 1H), 8.32- 8.25(m, 1H), 8.23-8.12 (m, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.73 (t, J = 9.0Hz, 1H), 7.55 (dd, J = 7.9, 4.7 Hz, 1H), 3.20 (d, J = 4.3 Hz, 3H). DMSO   95 Method AQ2, AP 356.4 (M + 1) Method C 1587 1H-NMR (300 MHz, DMSO):δ 9.65 (s, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.72-8.57 (m, 2H), 8.24 (d, J= 8.7 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 3.0 Hz, 1H), 7.76(d, J = 8.0 Hz, 1H), 7.53 (t, J = 10.9 Hz, 2H), 7.45-7.36 (m, 1H), 3.99(s, 3H), 3.94 (s, 3H), 3.21 (d, J = 4.1 Hz, 3H). DMSO    95 Method AQ2,AP 401.5 (M + 1) Method C 1588 2HCl 1H-NMR (300 MHz, DMSO): δ 10.77 (s,1H), 9.66 (s, 1H), 9.06 (s, 2H), 8.95 (d, J = 3.8 Hz, 1H), 8.38 (d, J =8.8 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H), 7.71 (d, J = 8.1Hz, 1H), 7.38 (dd, J = 22.8, 11.6 Hz, 2H), 4.03 (s, 3H), 3.31 (d, J =4.1 Hz, 3H). DMSO    95 Method AQ2, AP 361.5 (M + 1) Method C 1589 2HCl1H-NMR (300 MHz, DMSO): δ 10.23-10.05 (m, 1H), 9.64 (s, 1H), 9.00 (s,1H), 8.94 (s, 1H), 8.89 (s, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.14 (d, J =8.5 Hz, 1H), 7.85 (s, 1H), 7.36 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 10.9Hz, 1H), 3.90 (s, 1H), 3.30 (d, J = 4.3 Hz, 3H). DMSO    95 Method AQ2,AP 361.5 (M + 1) Method C 1590 2HCl 1H-NMR (300 MHz, DMSO): δ 10.34 (s,1H), 9.70 (s, 1H), 9.14 (d, J = 7.4 Hz, 1H), 8.98 (d, J = 3.9 Hz, 1H),8.75 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.93(d, J = 4.8 Hz, 1H), 7.27 (dd, J = 19.5, 6.3 Hz, 3H), 3.88 (s, 3H), 3.28(d, J = 4.1 Hz, 3H). DMSO    95 Method AQ2, AP 361.3 (M + 1) Method C1591 2HCl 1H-NMR (300 MHz, DMSO): δ 10.21 (s, 1H), 9.66 (d, J = 1.6 Hz,1H), 9.04 (d, J = 7.3 Hz, 1H), 8.96 (d, J = 3.5 Hz, 1H), 8.67 (s, 1H),8.28-8.12 (m, 2H), 7.88 (s, 1H), 7.66 (t, J = 8.8 Hz, 1H), 7.11- 6.97(m, 2H), 3.86 (s, 3H), 3.30 (d, J = 4.4 Hz, 3H). DMSO    95 Method AQ2,AP 361.3 (M + 1) Method C 1592 3HCl 1H-NMR (300 MHz, DMSO): δ 10.77 (s,1H), 9.69 (s, 1H), 9.39 (s, 1H), 9.16 (d, J = 7.8 Hz, 1H), 9.04 (s, 1H),8.97 (d, J = 3.6 Hz, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.53 (s, 2H), 8.31(d, J = 8.5 Hz, 1H), 7.91 (d, J = 5.4 Hz, 1H), 4.11 (s, 3H), 3.30 (d, J= 4.4 Hz, 3H). DMSO    95 Method AQ2, AP 343.1 (M + 1) Method C 15932HCl DMSO    95 Method AQ2, AP 359.1 (M + 1) Method C 1594 1H-NMR (300MHz, DMSO): δ 9.64 (d, J = 1.3 Hz, 1H), 8.82- 8.75 (m, 1H), 8.68 (dd, J= 4.8, 1.7 Hz, 1H), 8.60 (s, 1H), 8.53 (d, J = 1.7 Hz, 1H), 8.10 (dd, J= 8.7, 1.9 Hz, 1H), 7.86-7.77 (m, 4H), 7.58-7.48 (m, 2H), 7.09 (d, J =8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 1H), 3.99 (d, J = 6.0 Hz, 2H), 3.18(d, J = 4.4 Hz, 3H), 1.82- 1.69 (m, 2H), 1.07 (d, J = 6.7 Hz, 3H). DMSO   95 Method AQ2, AP 371.1 (M + 1) Method C 1595 2HCl 1H-NMR (300 MHz,DMSO): δ 10.24-10.10 (bs, 1H), 9.65 (s, 1H), 9.02 (s, 1H), 8.96 (d, J =3.8 Hz, 1H), 8.90 (s, 1H), 8.39 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H),7.98 (s, 1H), 7.89 (s, 1H), 7.54 (t, J = 9.1 Hz, 1H), 3.70 (bs, 4H),3.59 (bs, 4H), 3.32 (d, J = 4.4 Hz, 3H). DMSO    95 Method AQ2, AP 443.5(M + 1) Method C 1596 2HCl 1H-NMR (300 MHz, DMSO): δ 10.37 (s, 1H), 9.69(d, J = 1.7 Hz, 1H), 9.10 (d, J = 7.0 Hz, 1H), 9.03-8.93 (m, 2H), 8.42(d, J = 8.6 Hz, 1H), 8.28 (d, J = 9.3 Hz, 1H), 8.05 (d, J = 3.5 Hz, 1H),7.99 (dd, J = 6.2, 2.4 Hz, 2H), 7.52 (t, J = 9.1 Hz, 1H), 3.54- 3.43 (m,4H), 3.30 (t, J = 10.4 Hz, 3H), 1.98-1.81 (m, 4H). DMSO    95 MethodAQ2, AP 428.5 (M + 1) Method C 1597 2HCl 1H-NMR (300 MHz, DMSO): δ 10.71(s, 1H), 8.96 (d, J = 3.9 Hz, 1H), 8.81 (s, 1H), 8.74 (d, J = 7.9 Hz,1H), 8.36 (d, J = 8.7 Hz, 1H), 8.29-8.19 (m, 2H), 7.87 (dd, J = 6.5, 4.7Hz, 1H), 7.80 (dd, J = 15.5, 8.9 Hz, 1H), 7.61-7.50 (m, 1H), 7.36 (d, J= 8.1 Hz, 1H), 3.37 (d, J = 4.5 Hz, 3H). DMSO    95 Method AQ2, AP 349.4(M + 1) Method C 1598 1H-NMR (300 MHz, DMSO): δ 9.27 (d, J = 1.5 Hz,1H), 8.61 (dd, J = 12.6, 3.0 Hz, 2H), 8.41 (d, J = 2.9 Hz, 1H),8.34-8.27 (m, 1H), 8.16 (dd, J = 8.7, 1.9 Hz, 1H), 7.86 (d, J = 8.7 Hz,1H), 7.45 (dd, J = 16.0, 9.2 Hz, 3H), 7.05-6.97 (m, 1H), 3.96 (s, 3H),3.87 (s, 3H), 3.19 (d, J = 4.3 Hz, 3H). DMSO    95 Method AQ2, AP 373.4(M + 1) Method C 1599 2HCl 1H-NMR (300 MHz, DMSO): δ 10.44-10.13 (m,1H), 9.65 (s, 1H), 9.02 (s, 1H), 8.96 (d, J = 3.5 Hz, 1H), 8.87 (s, 1H),8.37 (d, J = 9.1 Hz, 1H), 8.24 (s, 1H), 7.86 (s, 2H), 7.78 (d, J = 7.9Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H), 4.64 (s,2H), 3.33 (d, J = 4.2 Hz, 3H), 3.17 (s, 1H). DMSO    95 Method AQ2, AP343.5 (M + 1) Method C 1600 MSA 1H-NMR (300 MHz, DMSO): δ 9.90 (s, 1H),9.57 (d, J = 1.6 Hz, 1H), 8.93 (dd, J = 5.0, 1.5 Hz, 2H), 8.73 (s, 1H),8.32 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.85 (dd, J = 10.1,7.0 Hz, 2H), 7.73 (d, J = 7.5 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.42(d, J = 7.5 Hz, 1H), 4.63 (s, 2H), 3.30 (d, J = 4.3 Hz, 3H), 2.32 (s,3H). DMSO    95 Method AQ2, AP 343.5 (M + 1) Method C 1601 MsOH ¹H NMR(300 MHz, DMSO) δ 9.72 (brs, 1H), 9.58 (d, J = 1.6 Hz, 1H), 9.03-8.89(m, 2H), 8.45 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 7.99-7.84 (m, 2H), 7.64(ddd, J = 9.2, 6.1, 3.1 Hz, 1H), 7.58- 7.31 (m, 2H), 3.28 (d, J = 4.5Hz, 3H), 2.39 (s, 3H). DMSO    98 G2/AQ3 1602 ¹H NMR (300 MHz, DMSO) δ9.59 (d, J = 2.0 Hz, 1H), 9.33 (s, 2H), 9.24 (s, 1H), 8.79 (d, J = 1.5Hz, 1H), 8.76-8.64 (m, 2H), 8.30 (dd, J = 8.7, 1.5 Hz, 1H), 8.12 (brs,2H), 7.91 (d, J = 8.7 Hz, 1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H). DMSO   98 G2/AQ3 1603 ¹H NMR (300 MHz, DMSO) δ 9.64- 9.53 (m, 1H), 8.77-8.53(m, 2H), 8.53 (s, 1H), 8.43 (d, J = 1.5 Hz, 1H), 8.11 - 7.90 (m, 3H),7.82 (d, J = 8.7 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 4.00 (s, 3H),3.98 (s, 3H). DMSO    98 G2/AQ3 1604 ¹H NMR (300 MHz, DMSO) δ 9.59 (d, J= 2.0 Hz, 1H), 8.83-8.66 (m, 2H), 8.55 (s, 1H), 8.27-7.99 (m, 4H),7.99-7.82 (m, 2H), 7.77 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H),7.56 (dd, J = 7.9, 4.8 Hz, 1H). DMSO    98 G2/AQ3 1605 1H NMR (300 MHz,DMSO) δ 9.58 (d, J = 2.1 Hz, 1H), 8.80-8.64 (m, 2H), 8.25 (dd, J = 8.7,1.6 Hz, 1H), 8.10 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 8.3 Hz, 2H), 7.88(d, J = 8.7 Hz, 1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H). DMSO    98 G2/AQ31606 2HCl ¹H NMR (300 MHz, DMSO) δ 9.95- 9.43 (m, 3H), 9.05 (d, J = 8.2Hz, 1H), 8.99 (dd, J = 5.1, 1.5 Hz, 1H), 8.74 (s, 1H), 8.33 (d, J = 8.7Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 7.93 (dd, J = 8.0, 5.1 Hz, 1H), 7.79(td, J = 8.9, 6.6 Hz, 1H), 7.51 (ddd, J = 11.5, 9.3, 2.6 Hz, 1H), 7.33(td, J = 8.3, 1.9 Hz, 1H). DMSO    98 G2/AQ3 1607 3HCl ¹H NMR (300 MHz,DMSO) δ 11.88 (s, 1H), 9.77 (d, J = 1.7 Hz, 1H), 9.56-9.28 (rn, 1H),9.19- 9.01 (m, 1H), 8.31-8.11 (m, 4H), 7.75-7.47 (m, 2H), 7.47- 7.23 (m,1H), 4.83-4.67 (m, 2H), 3.96 (t, J = 12.2 Hz, 2H), 3.57 (d, J = 11.9 Hz,2H), 3.46- 3.19 (m, 2H), 2.83 (d, J = 3.1 Hz, 3H). DMSO    98 G2/AQ31608 HCl ¹H NMR (300 MHz, DMSO) δ 14.45 (s, 1H), 10.36 (s, 1H), 9.31 (d,J = 2.2 Hz, 1H), 8.82 (s, 1H), 8.73 (ddd, J = 8.8, 2.5, 0.9 Hz, 1H),8.36 (d, J = 9.0 Hz, 1H), 8.16 (d, J = 3.4 Hz, 1H), 7.56- 7.36 (m, 3H),7.11 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 7.1 Hz, 1H), 3.99 (s, 3H), 3.87(s, 3H), 3.30 (d, J = 3.9 Hz, 3H). DMSO   100 Method AQ2/BF 1609 HCl ¹HNMR (300 MHz, DMSO) δ 10.97 (s, 1H), 9.56-9.35 (m, 2H), 9.04-8.81 (m,2H), 8.66 (t, J = 7.7 Hz, 1H), 8.61-8.45 (m, 2H), 8.15 (d, J = 8.6 Hz,1H), 8.10-7.96 (m, 1H), 7.77-7.58 (m, 1H), 3.25 (d, J = 4.1 Hz, 3H).DMSO   100 Method AQ2/BF 1610 2 MsOH ¹H NMR (300 MHz, CDCl₃) δ 9.93(brs, 1H), 9.61 (d, J = 1.8 Hz, 1H), 9.10-8.96 (m, 2H), 8.64 (s, 1H),8.21 (d, J = 8.7 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.99 (dd, J = 8.0,5.3 Hz, 1H), 7.69- 7.47 (m, 2H), 7.47-7.34 (m, 1H), 3.30 (d, J = 4.5 Hz,3H), 2.42 (s, 6H). DMSO >98 G2/AQ3 Method 3 1611 2HCl ¹H NMR (300 MHz,CDCl₃) δ 10.42 (brs, 1H), 9.71 (d, J = 1.9 Hz, 1H), 9.17 (d, J = 8.1 Hz,1H), 8.99 (dd, J = 5.1, 1.3 Hz, 1H), 8.78 (s, 1H), 8.33 (d, J = 8.7 Hz,1H), 8.17 (d, J = 8.7 Hz, 1H), 7.94 (dd, J = 8.1, 5.2 Hz, 1H), 7.79 (td,J = 8.9, 6.7 Hz, 1H), 7.55-7.37 (m, 1H), 7.31 (td, J = 3.4, 2.2 Hz, 1H),3.29 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3 1612 HCl ¹H NMR (300 MHz,DMSO) δ 9.95 (brs, 1H), 9.65 (s, 1H), 9.18- 9.02 (m, 1H), 8.95 (d, J =4.7 Hz, 1H), 8.58 (d, J = 8.7 Hz, 1H), 8.28 (s, 1H), 8.09-7.70 (m, 4H),3.29 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3 1613 ¹H NMR (300 MHz, DMSO) δ9.64 (d, J = 1.5 Hz, 1H), 8.77 (dt, J = 7.9, 1.9 Hz, 1H), 8.69 (dd, J =4.8, 1.7 Hz, 1H), 8.61-8.48 (m, 1H), 8.31 (d, J = 8.7 Hz, 1H), 8.11 (d,J = 1.8 Hz, 1H), 8.00- 7.83 (m, 3H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H),3.17 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3 1614 ¹H NMR (300 MHz, DMSO) δ9.65 (dd, J = 2.1, 0.8 Hz, 1H), 8.78 (dt, J = 8.0, 1.9 Hz, 1H), 8.69(dd, J = 4.8, 1.7 Hz, 1H), 8.65- 8.50 (m, 1H), 8.33 (d, J = 8.6 Hz, 1H),8.04-7.85 (m, 1H), 7.69 (dt, J = 8.5, 1.8 Hz, 1H), 7.65- 7.37 (m, 3H),3.18 (d, J = 4.5 Hz, 3H). DMSO >98 G2/AQ3 Method 3 1615 ¹H NMR (300 MHz,DMSO) δ 9.65 (d, J = 1.7 Hz, 1H), 8.84-8.74 (m, 1H), 8.69 (dd, J = 4.7,1.5 Hz, 1H), 8.65-8.52 (m, 1H), 8.34 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H),7.72 (d, J = 8.5 Hz, 1H), 7.69-7.43 (m, 3H), 3.18 (d, J = 4.3 Hz, 3H).DMSO >98 G2/AQ3 Method 3 1760 2 HCl ¹H NMR (400 MHz, DMSO) δ 10.04 (s,1H), 9.65 (s, 1H), 9.11- 8.99 (m, 1H), 8.96 (dd, J = 5.0, 1.4 Hz, 1H),8.41 (s, 1H), 8.13- 8.05 (m, 1H), 7.92-7.82 (m, 1H), 7.64-7.55 (m, 1H),7.44- 7.26 (m, 3H), 3.27 (d, J = 4.6 Hz, 3H), 2.47 (s, 3H). DMSO >98 AQ5ND 4

6-(3-methoxyphenyl)-2-(pyridine-3-yl)quinazoline-4-ol (lix-a)

6-(3-methoxyphenyl)-2-(pyridine-3-yl)quinazoline-4-ol was prepared from6-bromo-2-(pyridin-3-yl)quinazolin-4-ol (synthesized following Scheme 70substituting 2-amino-5-bromobenzamide for2-amino-5-bromo-3-methylbenzamide) and 3-methoxylphenylboronic acid asdescribed in Scheme 72 using method AQ2. The resultant product,6-(6-methoxypyridin-3-yl)-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine,was a pale yellow solid (19.1 mg, 51%). LCMS m/z=344 (M+1) (Method C)(retention time=2.01 min). ¹H NMR (300 MHz, DMSO) δ 9.64 (d, J=1.3 Hz,1H), 8.84-8.74 (m, 1H), 8.68 (dd, J=6.2, 1.7 Hz, 2H), 8.57 (d, J=1.6 Hz,2H), 8.16 (ddd, J=14.4, 8.7, 2.2 Hz, 2H), 7.85 (d, J=8.7 Hz, 1H), 7.54(dd, J=7.9, 4.8 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 3.93 (s, 3H), 3.18 (d,J=4.3 Hz, 3H).

Method AP:6-(3-methoxyphenyl)-2-(pyridine-3-yl)-4-(pyrrolidin-1-yl)quinazoline(Iviii-g)

6-(3-methoxyphenyl)-2-(pyridine-3-yl)-4-(pyrrolidin-1-yl)quinazoline wasprepared from 6-(3-methoxyphenyl)-2-(pyridine-3-yl)quinazoline-4-01 andpyrrolidine in a manner analogous to that described for6-bromo-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine using Method AP inScheme 72.6-(3-methoxyphenyl)-2-(pyridine-3-yl)-4-(pyrrolidin-1-yl)quinazoline wasa pale yellow solid (43 mg, 31%), LCMS m/z=383 (M+1) (Method C)(retention time=2.49 ruin). ¹H NMR (300 MHz, DMSO) δ 9.62 (s, 1H), 8.94(d, J=5.0 Hz, 2H), 8.56 (s, 1H), 8.32 (dd, J=19.9, 8.5 Hz, 2H), 7.83 (s,1H), 7.56-7.30 (m, 3H), 7.04 (d, J=6.8 Hz, 1H), 4.2.7 (s, 4H), 3.86 (s,3H), 2.08 (s, 4H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 76, replacing pyrrolidine with theappropriate amine and 3-methoxyphenylboronic acid with the appropriateboronic acid.

TABLE 25 Meth- od for Num- ¹H-NMR Retention LCMS Purity Coup- berProduct Salt ¹H-NMR Solvent LCMS Time Protocol Percent ling 1616

HCl 1H NMR (300 MHz, DMSO) δ 9.82 (s, 1H), 9.59 (s, 1H), 9.08-8.81 (m,3H), 8.36 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.95- 7.77 (rn,1H), 7.58-7.37 (m, 3H), 7.05 (d, J = 6.5 Hz, 1 H), 5.01-4.79 (m, 1H),3.87 (s, 3H), 1.42 (d, J = 6.5 Hz, 6H). DMSO 371   (M + 1) 2.36 Method C100 Meth- od AP 1617

HCl 1H NMR (300 MHz, DMSO) δ 10.38 (s, 1H), 9.64 (s. 1H), 9.43 (s, 1H),9.28 (s, 1H), 9.07 (d. J = 7.9 Hz, 1H), 9.00-8.76 (m, 3H), 8.48 (d, J =7.5 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.08-7.95 (m, 1H), 7.94-7.81 (m,1H), 3.97-3.74 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H). DMSO 328   (M + 1)1.82 Method C 100 Meth- od AP 1618

HCl 1H NMR (300 MHz, DMSO) δ 10.11 (s, 1H), 9.58 (s, 1H), 9.03-8.79 (m,3H), 8.35 (d, J = 8.7 Hz, 1H), 8.23-8.09 (m, 1H), 7.90-7.75 (m, 1H),7.58-7.36 (m, 3H), 7.04 (d, J = 3.3 Hz, 1H), 3.88 (s, 3H), 3.65 (t, J =6.0 Hz, 2H), 2.29-2.09 (m, 1H), 1.02 (d, J = 6.7 Hz, 6H). DMSO 385  (M + 1) 1.76 Method D 100 Meth- od AP 1619

HCl 1H NMR (300 MHz, DMSO) δ 9.83-9.52 (m, 2H), 9.27 (d, J = 7.1 Hz,1H), 8.95 (d, J = 5.1 Hz, 1H), 8.87 (s, 1H), 8.32 (d, J = 8.9 Hz, 1H),8.15-7.92 (m, 2H), 7.59-7.33 (m, 3H), 7 04 (d, J = 3.4 Hz, 1H),4.86-4.57 (m, 2H), 3.88 (s, 3H). DMSO 411   (M + 1) 1.99 Method D 100Meth- od AP 1620

HCl 1H NMR (300 MHz, DMSO) δ 10.50 (s, 1H), 9.64 (d, J = 1.4 Hz, 1H),9.12-8.85 (m, 3H), 8.46-8.33 (m, 1H), 8.27 (d, J = 8.9 Hz, 1H), 7.88(dd, J = 7.9, 5.1 Hz, 1H), 7.57-7.37 (m, 3H), 7.11-6.94 (m, 1H),4.00-3.76 (m, 5H), 1.37 (t, J = 7.2 Hz, 3H). DMSO MS not work 1.56Method D 100 Meth- od AP 1621

1H NMR (300 MHz, DMSO) δ 9.57 (s, 1H), 8.78-8.50 (m, 3H), 8.33-7.89 (m,3H), 7.83 (d, J = 8.7 Hz, 1H), 7.53 (dd, J = 7.9, 4.8 Hz, 1H), 7.47-7.32(m, 3H), 7.04-6.91 (m, 1H), 3.86 (s, 3H). DMSO 329   (M + 1) 1.47 MethodD 100 Meth- od AP 1622

HCl 1H NMR (300 MHz, DMSO) δ 9.65 (s, 1H), 9.14-8.87 (m, 2H), 8.50 (s,1H), 8.33 (s, 2H), 7.94-7.77 (m, 1H), 7.52-7.25 (m, 3H), 7.02 (d, J =7.9 Hz, 1H), 3.84 (s, 3H), 3.71 (s, 6H). DMSO 357   (M + 1) 1.55 MethodD 100 Meth- od AP 1623

1H NMR (300 MHz, DMSO) δ 9.60 (d, J = 1.4 Hz, 1H), 8.81-8.55 (m, 3H),8.42 (d, J = 1.8 Hz, 1H), 8.11 (ddd, J = 18.8, 8.7, 2.2 Hz, 2H), 7.86(d, J = 8.7 Hz, 1H), 7.52 (dd, J = 7.9, 4.8 Hz, 1H), 6.95 (d, J = 8.6Hz, 1H), 4.27 (s, 4H), 3.92 (s, 3H), 2.08 (s, 4H). DMSO 384.1 (M + 1)2.33 Method C 100 Meth- od AP 1624

2HCl 1H NMR (300 MHz, DMSO) δ 9.62 (s, 1H), 8.94 (d, J = 5.0 Hz, 2H),8.56 (s, 1H), 8.32 (dd, J = 19.9, 8.5 Hz, 2H), 7.83 (s, 1H), 7.56- 7.30(m, 3H), 7.04 (d, J = 6.8 Hz, 1H), 4.27 (s, 4H), 3.86 (s, 3H), 2.08 (s,4H). DMSO 383.2 (M + 1) 2.47 Method C 95 Meth- od AP 1625

1H NMR (300 MHz, DMSO) δ 9.70 (d, J = 1.4 Hz, 1H), 8.35 (d, J = 7.9 Hz,1H), 8.80- 8.72 (m, 2H), 8.45 (d, J = 8.7 Hz, 1H), 8.27 (dd J = 14.9,5.9 Hz. 3H), 7.63 (dd. J = 7.3, 4.8 Hz, 1H), 7.52-7.33 (m, 4H), 7.04 (d,J = 7.1 Hz, 1H), 3.88 (s, 3H). DMSO 380.1 (M + 1) 2.01 Method C 100Meth- od AP 1626

HCl 1H NMR (300 MHz, DMSO) δ 9.61 (s, 1H), 8.75 (d, J = 7.7 Hz, 1H),8.68 (d, J = 4.6 Hz, 1H), 8.30 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.89(d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.54 (dd, J = 7.6, 5.0Hz, 1H), 7.07 (d, J = 8.7 Hz, 2H), 3.82 (s, 4H), 3.49 (s, 7H). DMSO358.0 (M + 1) 2.25 Method C 100 Meth- od AP 1627

HCl 1H NMR (300 MHz, DMSO) δ 9.52 (s, 1H), 8.76 (d, J = 7.9 Hz, 1H),8.73-8.66 (m, 1H), 8.19-8.09 (m, 2H), 7.97 (d, J = 8.6 Hz, 1H),7.82-7.73 (m, 2H), 7.61-7.52 (m, 1H), 7.14-7.05 (m, 2H), 3.94 (s, 5H),3.89-3.80 (m, 9H). DMSO 399.2 (M + 1) 2.19 Method C 100 Meth- od AP 1628

1H NMR (300 MHz, DMSO) δ 9.55 (dd, J = 2.1, 0.8 Hz, 1H), 8.76-8.62 (m,3H), 8.60 (d, J = 1.7 Hz, 1H), 8.24-8.10 (m, 2H), 8.02 (s, 2H), 7.83 (d,J = 8.7 Hz, 1H), 7.58-7.46 (m, 1H), 6.98 (d, J = 9.2 Hz, 1H), 3.91 (s,3H). DMSO 330.1 (M + 1) 1.72 Method C 100 Meth- od AP 1629

1H NMR (300 MHz, DMSO) δ 9.65 (d, J = 2.1 Hz, 1H), 8.79 (d, J = 8.0 Hz,1H), 8.73 (dd, J = 4.7, 1.6 Hz, 1H), 8.36-8.25 (m, 2H), 8.06 (d, J = 8.7Hz, 1H), 7.59 (dd, J = 7.6, 4.4 Hz, 1H), 7.48-7.40 (m, 1H), 7.41-7.29(m, 2H), 7.01 (dd, J = 8.0, 2.4 Hz, 1H), 4.80 (q, J = 7.1 Hz, 2H), 3.85(s, 3H), 1.53 (t, J = 7.0 Hz, 3H). DMSO 358   (M + 1) Method C 99 Meth-od AP 1630

2 HCl 1H NMR (300 MHz, DMSO) δ 9.68 (d, J = 1.8 Hz, 1H), S.07 (d, J =5.5 Hz, 1H), 8.96 (d, J = 3.5 Hz, 1H), 8.30 (s, 1H), 8.37 (d, J = 7.5Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.94-7.83 (m, 1H), 7.57-7,39 (m, 3H),7.22 (d, J = 1.0 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 6.72 (s, 1H),5.18-5.04 (m, 1H), 3.88 (s, J = 2.7 Hz, 3H), 3.23 (dd, J = 13.7, 6.1 Hz,1H), 2.31- 2.17 (m, 1H), 2.17-1.88 (m, 4H), 1.74-1.55 (m, 1H). DMSO440.6 (M + 1) Method C 99 Meth- od AP 1631

2 HCl 1H NMR (300 MHz, DMSO) δ 9.70 (d, J = 1.6 Hz, 1H), 9.24 (d, J =7.4 Hz, 1H), 8.99 (dd, J = 5.3, 1.4 Hz, 1H), 8.34 (dd, J = 15.7, 6.1 Hz,3H), 8.21 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 7.7, 5.1 Hz, 1H), 7.51-7.33(m, 3H), 7.04 (dd, J = 7.8, 2.4 Hz, 1H), 4.67 (s, 2H), 4.33 (s, 2H),3.87 (s, J = 3.6 Hz, 3H), 3.50 (s, 2H). DMSO 412.4 (M + 1) Method C 99Meth- od AP 1632

2 HCl 1H NMR (300 MHz, DMSO) δ 9.00 (d, J = 6.5 Hz, 2H), 8.78 (d, J =6.5 Hz, 2H), 8.46- 8.32 (m, 2H), 8.15 (d, J = 8.4 Hz, 1H), 7.53- 7.30(m, 3H), 7.02 (d, J = 7.8 Hz, 1H), 4.34 (s, J = 2.4 Hz. 3H), 3.86 (s, J= 2.5 Hz, 3H). DMSO 344.4 (M + 1) Method C 99 Meth- od AP 1633

1H NMR (300 MHz, DMSO) δ 9.55 (dd, J = 2.1, 0.8 Hz, 1H), 8.76-8.62 (m,3H), 8.60 (d, J = 1.7 Hz, 1H), 8.24-8.10 (m, 2H), 8.02 (s, 2H), 7.83 (d,J = 8.7 Hz, 1H), 7.56-7.46 (m, 1H), 6.98 (d, J = 9.2 Hz, 1H), 3.91 (s,3H). DMSO 330.1 (M + 1) Method C 99 Meth- od AP ¹H Num- StartingStarting Salt NMR ber Material R¹ Material R³ Product Type ¹H NMRSolvent 1634

¹H NMR (DMSO-d₆) ppm 3.87 (s, 3H), 4.76 (d, 2H, J = 5.4 Hz), 6.58 (d,1H, J = 1.1 Hz), 7.00-7.75 (m, 8H), 7.85 (d, 1H, J = 8.6 Hz), 8.64-8.97(m, 4H), 9.64 (s, 1H) DMSO 1635

¹H NMR (DMSO-d₆) ppm 3.34- 3.95 (m, 11H), 7.01 (d, 1H, J = 8.1 Hz),7.32- 7.45 (m, 3H), 7.56 (dd, 1H, J = 6.1, 8.1 Hz), 7.97 (d, 1H, J = 8.2Hz), 8.16- 8.76 (m, 4H), 9.61 (s, 1H) DMSO 1636

¹H NMR (DMSO-d₆) ppm 2.23 (m, 2H), 3.85 (s, 3H), 4.71 (br s, 4H), 6.98(dd, 1H, J = 2.1, 8.0 Hz), 7.31-7.55 (m, 4H), 7.87 (d, 1H, J = 8.2 Hz),8.12- 8.74 (m, 4H), 9.59 (s, 1H) DMSO 1637

1H NMR (DMSO-d6) ppm 1.77 (br s, 6H), 3.86- 3.89 (br m, 7H), 6.99 (dd,1H, J = 1.4, 8.6 Hz), 7.31-7.57 (m, 4H), 7.93 (d, 1H, J = 1.4, 8.6 Hz),8.11-8.16 (m, 2H), 8.69-8.76 (m, 2H), 9.61 (s, 1H) DMSO 1638

1H NMR (DMSO-d6) ppm 2.18-2.22 (m, 1H), 3.00-3.09 (m, 1H), 3.11-3.22 (m,2H), 3.31-3.34 (m, 1H), 3.86 (s, 3H), 6.29- 6.31 (m, 1H), 7.17- 8.82 (m,14H), 9.63 (s, 1H) DMSO 1639

1H NMR (DMSO-d6) ppm 3.87 (s, 3H), 4.10-4.13 (m, 2H), 4.35-4.38 (m, 2H),6.92-7.46 (m, 10H), 7.85 (d, 1H, J = 8.6 Hz), 8.16 (d, 1H, J = 8.6 Hz),8.66- 8.75 (m, 4H), 3.61 (s, 1H) DMSO 1640

1H NMR (DMSO-d6) ppm 3.07 (t, 2H, J = 6.9 Hz), 3.87 (s, 3H), 3.92- 3.96(m, 2H), 7.00- 7.58 (m, 10H), 7.84 (d, 1H, J = 8.6 Hz), 8.14 (d, 1H, J =8.6 Hz), 8.59-8.78 (m, 4H), 9.64 (s, 1H) DMSO 1641

1H NMR (DMSO-d6) ppm 3.37 (s, 3H), 4.95 (d, 2H, J = 5.6 Hz), 7.01- 7.51(m, 10H), 7.85 (d, 1H, J = 8.6 Hz), 8.16 (d, 1H, J = 8.6 Hz), 8.65-8.73(m, 4H), 956 (s, 1H) DMSO 1642

1H NMR (DMSO-d6) ppm 1.66- 1.781 (m, 6H), 2.16-2.19 (m, 2H), 3.87 (s,3H), 4.78 (br s, 1H), 7.00-7.55 (m, 5H), 7.83 (d, 1H, J = 8.6 Hz), 8.12(d, 1H, J = 8.6 Hz), 8.29 (s, 1H), 8.67- 8.77 (m, 3H), 9.62 (s, 1H) DMSO1643

HCl 1H NMR (DMSO-d6) ppm 0.81 (t, 3H, J = 7.4 Hz), 1.47- 1.54 (m, 2H),2.00- 2.05 (m, 2H), 3.32- 3.37 (m, 4H), 3.86- 3.91 (m, 5H), 7.03- 7.80(m, 5H), 8.16 (d, 1H, J = 8.7 Hz), 8.34 (d, 1H, J = 8.7 Hz), 8.86- 8.96(m, 3H), 9.61 (s, 1H), 10.03 (s, 1H) DMSO 1644

1H NMR (DMSO-d6) ppm 0.38-0.54 (m, 4H), 1.30-1.32 (m, 1H), 3.58-3.62 (m,2H), 3.87 (s, 3H), 7.00- 7.54 (m, 5H), 7.86 (d, 1H, J = 8.6 Hz), 8.14(d, 1H, J = 8.6 Hz), 8.64-8.76 (m, 4H), 9.62 (s, 1H) DMSO 1645

1H NMR (DMSO-d6) ppm 1.83-1.88 (m, 2H), 2.21-2.27 (m, 2H), 2.43 (br s,2H), 3.87 (s, 3H), 4.88-4.91 (m, 1H), 7.03-7.57 (m, 5H), 7.83 (d, 1H, J= 8.6 Hz), 8.13 (d, 1H, J = 8.6 Hz), 8.62-8.77 (m, 4H), 9.63 (s, 1H)DMSO 1646

1H NMR (DMSO-d6) ppm 3.21 (s, 1H), 3.88 (s, 3H), 4.52 (dd, 2H, J = 2.2,5.2 Hz), 7.01- 7.58 (m, 5H), 7.88 (d, 1H, J = 8.7 Hz), 8.19 (d, 1H, J =8.6 Hz), 8.64- 9.01 (m, 4H), 9.66 (s, 1H) DMSO 1647

1H NMR (DMSO-d6) ppm 3.87 (s, 3H), 4.37 (br s, 2H), 5.19 (dd, 1H, J =1.5, 10.2 Hz), 5.31 (dd, 1H, J = 1.5, 17.2 Hz), 6.01- 6.22 (m, 1H),7.00- 7.56 (m, 5H), 7.85 (d, 1H, J = 8.6 Hz), 8.16 (d, 1H, J = 8.6 Hz),8.67-8.82 (m, 4H), 9.61 (s, 1H) DMSO 1648

1H NMR (DMSO-d6) ppm 0.94- 0.99 (t, 6H, J = 7.4 Hz), 1.68-1.80 (m, 4H),3.87 (s, 3H), 4.49- 4.52 (m, 1H), 7.01- 7.47 (m, 5H), 7.83 (d, 1H, J =8.6 Hz), 8.11-8.15 (m, 2H), 8.67-8.75 (m, 3H), 9.63 (s, 1H) DMSO 1649

1H NMR (DMSO-d6) ppm 1.68 (s, 9H), 3.87 (s, 3H), 7.01- 7.70 (m, 6H),7.82 (d, 1H, J = 8.6 Hz), 8.11 (d, 1H, J = 8.6 Hz), 8.67- 8.74 (m, 3H),9.60 (s, 1H) DMSO 1650

1H NMR (DMSO-d6) ppm 0.97 (t, 3H, J = 7.2 Hz), 1.44- 1.48 (m, 2H), 1.74-1.78 (m, 2H), 3.71- 3.75 (m, 2H), 3.89 (s, 3H), 7.00- 7.56 (m, 5H), 7.83(d, 1H, J = 8.6 Hz), 8.15 (d, 1H, J = 8.6 Hz), 8.59- 8.76 (m, 4H), 9.62(s, 1H) DMSO 1651

1H NMR (DMSO-d6) ppm 3.87 (s, 3H), 4.98 (d, 2H, J = 5.6 Hz), 7.02-7.46(m, 7H), 7.87 (d, 1H, J = 8.7 Hz), 8.51 (dd, 1H, J = 1.5, 4.5 Hz),8.50-8.71 (m, 5H), 9.26 (s, 1H), 9.48 (s, 1H) DMSO 1652

1H NMR (DMSO-d6) ppm 3.87 (s, 3H), 4.93 (d, 2H, J = 5.5 Hz), 7.00- 7.46(m, 6H), 7.86- 7.90 (m, 2H), 8.16 (d, 1H, J = 1.7 Hz), 8.46 (d, 1H, J =1.7 Hz), 8.66-8.76 (m, 4H), 9.22 (s, 1H), 9.56 (s, 1H) DMSO 1653

1H NMR (DMSO-d6) ppm 3.22-3.27 (m, 2H), 3.87 (s, 3H). 4.04- 4.11 (m,2H), 7.02- 7.46 (m, 8H), 7.83 (d, 1H, J = 8.6 Hz), 8.13 (d, 1H, J = 1.6Hz), 8.67- 8.78 (m, 5H), 9.64 (s, 1H) DMSO 1654

1H NMR (DMSO-d6) ppm 1.76-1.88 (m, 4H), 2.66 (br s, 1H), 3.37- 3.48 (m,2H), 3.86 (s, 3H), 4.39-4.47 (m, 2H), 6.95-7.57 (m, 7H), 7.95 (d, 1H, J= 8.7 Hz), 8.15- 8.19 (m, 2H), 8.69- 8.76 (m, 2H), 9,61 (s, 1H) DMSO1655

¹H NMR (DMSO-d₆) ppm 3.87 (s, 3H), 4.97 (d, 2H, J = 5.6 Hz), 7.00-7.50(m, 8H), 7.85 (d, 1H, J = 8.7 Hz), 8.16 (s, 1H), 8.66- 8.77 (m, 3H),9.11 (s, 1H), 9.61 (s, 1H) DMSO 1656

¹H NMR (DMSO-d₆) ppm 2.28 (s, 3H), 3.87 (s, 3H), 4.91 (d, 2H, J = 5.5Hz), 7.00-7.52 (m, 9H), 7.86 (d, 1H, J = 8.6 Hz), 8.17 (dd, 1H, J = 8.6,1.8 Hz), 8.66-9.16 (m, 3H), 9.18-9.16 (m, 1H), 9.57 (s, 1H) DMSO 1657

¹H NMR (DMSO-d₆) ppm 3.71 (s, 3H), 3.87 (s, 3H), 4.91 (d, 2H, J = 5.7Hz), 6.82-7.52 (m, 9H), 7.86 (d, 1H, J = 8.7 Hz), 8.17 (dd, 1H, J = 8.7,1.8 Hz), 8.66-9.15 (m, 3H), 9.17-9.19 (m, 1H), 9.57 (s, 1H) DMSO 1658

¹H NMR (DMSO-d₆) ppm 2.25 (s, 3H), 3.87 (s, 3H), 4.91 (d, 2H, J = 5.7Hz), 7.00-7.53 (m, 9H), 7.86 (d, 1H, J = 8.6 Hz), 8.17 (dd, 1H, J = 8.6,1.8 Hz), 8.66-9.15 (m, 3H), 9.17-9.19 (m, 1H), 9.57 (s, 1H) DMSO 1659

¹H NMR (DMSO-d₆) ppm 2.44 (s, 3H), 3.86 (s, 3H), 4.95 (d, 2H, J = 5.7Hz), 7.01-7.53 (m, 9H), 7.86 (d, 1H, J = 8.6 Hz), 8.17 (dd, 1H, J = 8.6,1.8 Hz), 8.65-9.02 (m, 3H), 9.50-9.52 (m, 1H), 9.54 (s, 1H) DMSO 1660

¹H NMR (DMSO-d₆) ppm 3.87 (s, 3H), 7.03 (s, 1H), 7.44- 7.94 (m, 10H),8.07- 8.70 (m, 4H), 9.41 (s, 1H) DMSO 1661

¹H NMR (DMSO-d₆) ppm 3.87 (s, 3H), 4.91 (d, 2H, J = 5.5 Hz), 7.00- 7.04(m, 1H), 7.04-7.55 (m, 7H), 7.87 (d, 1H, J = 8.6 Hz), 8.18 (dd, 1H, J =8.6, 1.8 Hz), 8.66- 9.18 (m, 3H), 9.18- 9.21 (m, 1H), 9.55 (s, 1H) DMSO1662

¹H NMR (DMSO-d₆) ppm 3.87 (s, 3H), 4.99 (d, 2H, J = 5.5 Hz), 7.01- 7.05(m, 2H), 7.15- 7.56 (m, 6H), 7.88 (d, 1H, J = 8.6 Hz), 8.20 (dd, 1H, J =8.6, 1.8 Hz), 8.64- 9.18 (m, 3H), 9.19- 9.21 (m, 1H), 9.50 (s, 1H) DMSO1663

¹H NMR (DMSO-d₆) ppm 3.49 (s, 3H), 3.74 (s, 3H), 5.15 (s, 2H), 6.90 (d,J = 8.2 Hz, 1H), 7.04- 7.29 (m, 2H), 7 33- 7.54 (m, 7H), 7.93 (d, 1H, J= 8.6 Hz), 8.15 (dd, 1H, J = 8.6, 1.8 Hz), 8.21 (s, 1H), 8.68- 8.75 (m,2H), 9.59 (s, 1H) DMSO 1664

¹H NMR (DMSO-d₆) ppm 3.87 (s, 3H), 4.94 (d, 2H, J = 5.5 Hz), 7.01- 7.03(m, 1H), 7.35- 7.57 (m, 7H), 7.88 (d, 1H, J = 8.6 Hz), 8.20 (dd, 1H, J =8.6, 1.8 Hz), 8.66- 9.22 (m, 3H), 9.19- 9.21 (m, 1H), 9.50 (s, 1H) DMSO1665

¹H NMR (DMSO-d₆) ppm 3.87 (s, 3H), 4.96 (d, 2H, J = 5.5 Hz), 7.00- 7.03(m, 2H), 7.33- 7.52 (m, 7H), 7.88 (d, 1H, J = 8.6 Hz), 8.19 (dd, 1H, J =8.6, 1.8 Hz), 8.65- 9.20 (m, 3H), 9.19- 9.21 (m, 1H), 9.54 (s, 1H) DMSO1666

¹H NMR (DMSO-d₆) ppm 3.87 (s, 3H), 4.93 (d, 2H, J = 5.5 Hz), 7.00- 7.19(m, 3H), 7.41- 7.55 (m, 6H), 7.88 (d, 1H, J = 8.6 Hz), 8.17 (dd, 1H, J =8.6, 1.8 Hz), 8.65- 9.18 (m, 3H), 9.13- 9.21 (m, 1H), 9.57 (s, 1H) DMSO1667

¹H NMR (DMSO-d₆) ppm 3.87 (s, 3H), 4.92 (d, 2H, J = 5.5 Hz), 7.01- 7.03(d, 1H, J = 7.0 Hz), 7.37-7.53 (m, 6H), 7.72 (d, 1H, J = 8.6 Hz), 8.18(dd, 1H, J = 8.6, 1.8 Hz), 8.66-9.19 (m, 3H), 9.20-9.23 (m, 1H), 9.56(s, 1H) DMSO 1668

¹H NMR (DMSO-d₆) ppm 1.68 (d, 3H, J = 7.0 Hz), 3.87 (s, 3H), 4.92 (d,2H, J = 5.5 Hz), 5.75-5.78 (m, 1H), 7.02 (d, 1H, J = 7.0 Hz), 7.32-7.56(m, 9H), 7.84 (d, 1H, J = 8.6 Hz), 8.15 (dd, 1H, J = 8.6, 1.8 Hz),8.64-8.84 (m, 4H), 9.51 (s, 1H) DMSO 1669

¹H NMR (DMSO-d₆) ppm 3.70 (s, 3H), 3.86 (s, 3H), 4.92 (d, J = 5.1 Hz,2H), 6.89-7.01 (m, 3H), 7.41-7.54 (m, 6H), 7.85 (d, J = 8.6 Hz, 1H),7.85 (d, J = 8.6 Hz, 1H), 8.67- 8.75 (m, 3H), 9.19 (s, 1H), 9.56 (s, 1H)DMSO 1670

¹H NMR (DMSO-d₆) ppm 3.87 (s, 3H), 3.91 (s, 3H), 4.92 (d, J = 5.0 Hz,2H), 6.87-7.52 (m, 9H), 7.85 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.5 Hz,1H), 8.64-8.73 (m, 3H), 9.05 (s, 1H), 9.52 (s, 1H) DMSO 1671

¹H NMR (DMSO-d₆) ppm 3.87 (s, 3H), 4.93 (d, J = 5.6 Hz, 2H), 7.02 (s,1H), 7.41-7.61 (m, 7H), 7.83 (d, J = 8.9 Hz, 1H), 8.18 (d, J = 8.9 Hz,1H), 8.66-8.71 (m, 3H), 9.21 (s, 1H), 9.54 (s, 1H) DMSO 1672

¹H NMR (DMSO-d₆) ppm 3.69 (s, 6H), 3.87 (s, 3H), 4.93 (d, J = 5.6 Hz,2H), 6.90 (s, 1H), 7.00- 7.54 (m, 7H), 7.85 (d, J = 8.6 Hz, 1H), 8.17(d, J = 8.6 Hz, 1H), 8.66- 8.78 (m, 3H), 9.14 (s, 1H), 9.63 (s, 1H) DMSO1673

— DMSO 1674

2HCl 1H—NMR (300 MHz, DMSO): δ 9.71 (d, J = 1.6 Hz, 1H), 9.16 (d, J =8.2 Hz, 1H), 8.98 (dd, J = 5.1, 1,5 Hz, 1H), 8.58 (s, 1H), 8 48- 8.34(m, 3H), 8.20 (ds J = 8.0 Hz, 1H), 7.98- 7.87 (m, 2H), 7.75 (t, J = 7.8Hz, 1H), 3.73 (s, 6H). DMSO 1675

1H—NMR (300 MHz, DMSO): δ 9.59 (s, 1H), 8.78- 8.62 (m, 2H), 8.38 (s,1H), 8.05 (dd, J = 8.6, 1.3 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.73 (d,J = 8.7 Hz, 2H), 7.52 (dd, J = 7.8, 4.7 Hz, 1H), 7.07 (d, J = 8.8 Hz,2H), 4.04 (s, 4H), 3.82 (s, 3H), 2.02 (3, 4H). DMSO 1676

3HCl 1H—NMR (300 MHz, DMSO): δ 10.40 (s, 1H), 9.48 (d, J = 2.0 Hz, 1H),8.95 (s, 2H), 3.88 (d, J = 5.2 Hz, 1H), 8.72 (d, J = 4.3 Hz, 1H), 8.35(d, J = 8.9 Hz, 1H), 8.18 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.94- 7.81(m, 2H), 7.64 (s, 1H), 7.54-7.45 (m, 3H), 7.06-7.00 (m, 1H), 5.25 (d, J= 5.1 Hz, 2H), 3.88 (s, 3H). DMSO 1677

1H—NMR (300 MHz, DMSO): δ 12.83 (s, 1H), 9.32 (d, J = 2.2 Hz, 1H), 8.77(dd, J = 4.8, 1.5 Hz, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.56- 8.49 (m, 1H),8.37 (d, J = 2.2 Hz, 1H), 8.23-8.14 (m, 2H), 7.85 (d, J = 8.5 Hz, 1H),7.60 (dd, J = 3.0, 4.8 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 3.92 (s, 3H).DMSO 1678 NH3

2HCl 1H NMR (300 MHz, DMSO) δ 9.79 (brs, 1H), 9,60 (s, 2H), 9.07 (d, J =7.4 Hz, 1H), 9.00 (d, J = 4.5 Hz, 1H), 8.80 (s, 1H), 3.35 (d, J = 8.7Hz, 1H), 8.26 (d, J = 8.6 Hz, 1H), 8.02- 7.88 (m, 1H), 7.67- 7.48 (m,2H), 7.43-7.37 (m, 1H). DMSO Meth- od of Num- Purity Coup- ber percentling 1634 >98 Meth- od AQ3, F5, G2 (re- flux) 1635 >98 Meth- od AQ3, F5,G2 (re- flux) 1636 >98 Meth- od AQ3, F5, G2 (re- flux) 1637 >98 Meth- odAQ3, F5, G2 (re- flux) 1638 >98 Meth- od AQ3, F5, G2 (re- flux) 1639 >98Meth- od AQ3, F5, G2 (re- flux) 1640 >98 Meth- od AQ3, F5, G2 (re- flux)1641 >98 Meth- od AQ3, F5, G2 (re- flux) 1642 >98 Meth- od AQ3, F5, G2(re- flux) 1643 >98 Meth- od AQ3, F5, G2 (re- flux) 1644 >98 Meth- odAQ3, F5, G2 (re- flux) 1645 >98 Meth- od AQ3, F5, G2 (re- flux) 1646 >98Meth- od AQ3, F5, G2 (re- flux) 1647 >98 Meth- od AQ3, F5, G2 (re- flux)1648 >98 Meth- od AQ3, F5, G2 (re- flux) 1649 >98 Meth- od AQ3, F5, G2(re- flux) 1650 >98 Meth- od AQ3, F5, G2 (re- flux) 1651 >98 Meth- odAQ3, F5, G2 (re- flux) 1652 >98 Meth- od AQ3, F5, G2 (re- flux) 1653 >98Meth- od AQ3, F5, G2 (re- flux) 1654 >98 Meth- od AQ3, F5, G2 (re- flux)1655 >98 Meth- od AQ3, F5, G2 (re- flux) 1656 >98 Meth- od AQ3, F5, G2(re- flux) 1657 >98 Meth- od AQ3, F5, G2 (re- flux) 1658 >98 Meth- odAQ3, F5, G2 (re- flux) 1659 >98 Meth- od AQ3, F5, G2 (re- flux) 1660 >98Meth- od AQ3, F5, G2 (re- flux) 1661 >98 Meth- od AQ3, F5, G2 (re- flux)1662 >98 Meth- od AQ3, F5, G2 (re- flux) 1663 >98 Meth- od AQ3, F5, G2(re- flux) 1664 >98 Meth- od AQ3, F5, G2 (re- flux) 1665 >98 Meth- odAQ3, F5, G2 (re- flux) 1666 >98 Meth- od AQ3, F5, G2 (re- flux) 1667 >98Meth- od AQ3, F5, G2 (re- flux) 1668 >98 Meth- od AQ3, F5, G2 (re- flux)1669 >98 Meth- od AQ3, F5, G2 (re- flux) 1670 >98 Meth- od AQ3, F5, G2(re- flux) 1671 >98 Meth- od AQ3, F5, G2 (re- flux) 1672 >98 Meth- odAQ3, F5, G2 (re- flux) 1673 95 Meth- od AQ3, AP 1674 95 Meth- od AQ3, AP1675 95 Meth- od AQ3, AP 1676 95 Meth- od AQ3, AP 1677 95 Meth- od AQ3,AP 1678 >98 Meth- od AQ3, F5, G2 (re- flux)

Method AT for Alkylation:Method AT1: NaOMe/MeOH/microwave/150° C.Method AT2: MeOH/microwave/150° C.Method AT3: DIPEA/KI/DMF/microwave/150° C.

Method AR: 3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol(lxi-a)

To a suspension of6-(3-methoxyphenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine(prepared in a similar method described for 6-(3-methoxyphenyl)-2-(pyridine-3-yl)-4-(pyrrolidin-1-yl)quinazoline using Scheme74, substituting N-methylamine for pyrrolidine) (1.00 g, 2.9 mmol) inCH₂Cl₂ (15 mL) and boron tribromide 1M solution in dichloromethane (8.76ml, 8.76 mmol) was added at 0° C. The reaction mixture was stirredovernight at room temperature after which it was carefully poured into avigorously stirring mixture of ice and saturated aqueous solution ofNaHCO₃. The resultant solid was collected by filtration, dried and thendissolved in a mixture of K₂CO₃ (2 g) and methanol (50 mL). The solutionwas then acidified using aqueous NH₄Cl solution. (50 mL) and theprecipitate which formed was collected by filtration and dried to give0.95 g of 3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol aspale yellow solid (99%). LCMS m/z=329 (M+1) (Method D) (retentiontime=1.30 min). ¹H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 9.60 (s, 1H),8.77 (d, J=8.0 Hz, 1H), 8.74-8.59 (m, 2H), 8.54 (s, 1H), 8.05 (d, J=8.7Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.54 (dd, J=7.9, 4.8 Hz, 1H), 7.38-7.12(m, 3H), 6.82 (d, J=7.8 Hz, 1H), 3.17 (d, J=4.3 Hz, 3H).

Method AS:6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine(lxii-a)

A suspension of3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol (0.30 g, 0.914mmol), 1-bromo-2-chloroethane (0.38 ml, 4.57 mmol), and potassiumcarbonate (0.38 g, 2.74 mmol) in DMF (10 mL) was stirred for 2 days atroom temperature. Water (10 mL) and ethyl acetate (10 mL) were added tothe mixture and extracted. The organic layer was separated andconcentrated in vacuo to leave a solid, which was collected byfiltration and washed with hexane and dried to give 0.30 g of6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amineas brown solid (83%). The product was used without further purification.

Method AT1:6-(3-(2-methoxyethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine(lxiii-a)

A solution of6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine(70 mg, 0.18 mmol) and sodium methoxide (97 mg, 1.8 mmol) in methanol (3mL) was placed in a microwave reaction vial. The mixture was heatedunder microwave irradiation conditions at 150° C. for 30 minutes afterwhich the solvent was removed in vacuo. The crude product was obtained,which was purified by column chromatography on basic silica gel (elutedwith hexane/ethyl acetate 3:1→1:4) to give 20 mg of6-(3-(2-methoxyethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amineas an off-white powder (29%). LCMS m/z=387 (M+1) (Method D) (retentiontime=1.49 min). ¹H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.77 (d, J=8.2Hz, 1H), 8.73-8.51 (m, 3H), 8.16 (d, J=8.7 Hz, 1H), 7.84 (d, J=8.3 Hz,1H), 7.60-7.32 (m, 4H), 7.01 (s, 1H), 4.21 (s, 2H), 3.70 (s, 2H), 3.33(s, 3H), 3.19 (s, 3H),

Method AT2:N-Methyl-6-(4-(2-morpholinoethoxy)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine(lxiii-b)

In a 10 mL microwave vial6-(4-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine(70.0 mg, 0.179 mmol) and morpholine (0.155 ml, 1.791 mmol) were addedin methanol (3 mL) to give a yellow suspension. The vial was irradiatedat 150° C. in the microwave for 30 min. The volatiles were evaporated invacuo. Water (10 mL) was added to the reaction mixture and extractedwith ethyl acetate (2×10 mL). The organic layers were combined andwashed with brine (1×20 mL), then dried over MgSO₄, filtered andconcentrated. The residue was purified by column chromatography on basicsilica gel (eluted with hexane/ethyl acetate 3:2 to 0:1). The productwas obtained as the parent and converted to the HCl salt by addition of4 M HCl-dioxane, then crystallized from EtOH-H2O to give 55 mg ofN-methyl-6-(4-(2-morpholinoethoxy)phenyl)-2-(pyridin-3-yl)quinazolin-4-amineas a yellow powder (60% yield), LCMS m/z=442 (M+1) (Method D) (retentiontime=1.12 min). ¹H NMR (300 MHz, DMSO) δ 11.31 (s, 1H), 10.41 (s, 1H),9.63 (s, 1H), 9.10-8.79 (m, 3H), 8.34 (d, J=8.2 Hz, 1H), 8.28-8.12 (m,1H), 7.92 (d, J=8.0 Hz, 2H), 7.87-7.74 (m, 1H), 7.18 (d, J=8.0 Hz, 2H),4.60-4.46 (m, 2H), 4.06-3.91 (m, 2H), 3.91-3.74 (m, 2H), 3.67-3.41 (m,4H), 3.38-3.09 (m, J=10.1 Hz, 5H).

Method AT3:N-methyl-2-(pyridin-3-yl)-6-(3-(2-(2,2,2trifluoroethylamino)ethoxy)phenyl)quinazolin-4-amine(lxiii-c)

In a 10 mL microwave vial was added6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine(50.0 mg, 0.128 mmol), 2,2,2-trifluoroethylamine (0.100 ml, 1.279 mmol),potassium iodide (42.5 mg, 0.256 mmol), and N,N′-diisopropylethylamine(0.045 ml, 0.256 mmol) in DMF (3 mL) to give a yellow suspension. Thevial was irradiated at 150° C. in the microwave for 20 min. Water (10mL) was added to the mixture and extracted with ethyl acetate (2×20 mL).The organic layers were combined and washed with water (1×20 mL) andbrine (1×20 mL), dried over MgSO₄, filtered and concentrated. Theresidue was purified by column chromatography on silica gel (eluted with(CH₂Cl₂/CH₂Cl₂-MeOH-NH₄OH=100:20:1 1:0 to 0:1). The product wasconverted to the HCl salt by addition of 4 M HCl-dioxane, thencrystallization from IPA-H2O to give 30 mg ofN-methyl-2-(pyridin-3-yl)-6-(3-(2-(2,2,2-trifluoroethylamino)ethoxy)phenyl)quinazolin-4-amineas a yellow powder (42%). LCMS m/z=454 (M+1) (Method C) (retentiontime=2.26 min). ¹H NMR (300 MHz, DMSO) δ 10.73-10.36 (m, 1H), 9.65 (s,1H), 9.13-8.98 (m, 2H), 8.93 (d, J=5.0 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H),8.24 (d, J=7.7 Hz, 1H), 7.94-7.75 (m, 1H), 7.69-7.41 (m, 3H), 7.09 (d,J=8.1 Hz, 1H), 4.61-4.43 (m, 2H), 4.28-4.07 (m, 2H), 3.59-3.39 (m, 2H),3.30 (d, J=2.8 Hz, 3H).

In a 50 mL round-bottomed flask was added6-(4-(2-aminoethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine(15.0 mg, 0.040 mmol) and triethylamine (0.017 ml, 0.121 mmol) in CH₂Cl₂(5 mL) to give a yellow solution. Acetic anhydride (4.58 μl, 0.048 mmol)was added and the mixture was stirred for 2 h at room temperature. Water(10 mL) was added to the mixture and extracted with ethyl acetate (2×10mL). The organic layers were combined and washed with brine (1×20 mL),dried over Mg₂SO₄, filtered and concentrated. The residue was purifiedby column chromatography on silica gel (eluted with CH₂Cl₂/MeOH 1:0 to9:1). The product was converted to the HCl salt by addition of 4 MHCl-dioxane, then dissolved in a small amount of methanol, followed byethyl acetate. The resulting solid was filtered and dried to give 10 mgofN-(2-(4-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenoxy)ethyl)acetamideas a HCl salt as a yellow solid in a 51% yield. LCMS m/z=414 (M+1)(Method C) (retention time=1.28 min). ¹H NMR (300 MHz, DMSO) δ 10.26 (s,1H), 9.62 (s, 1H), 9.06-8.90 (m, 2H), 8.81 (s, 1H), 8.34 (d, J=9.0 Hz,1H), 8.17 (d, J=6.6 Hz, 2H), 7.86 (d, J=8.0 Hz, 3H), 7.13 (d, J=7.91 Hz,2H), 4.06 (t, J=5.4 Hz, 2H), 3.52-3.38 (m, 2H), 3.30 (d, J=4.1 Hz, 3H),1.84 (s, 3H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 78, replacing 1-bromo-2-chloroethane withthe corresponding alkyl halide.

TABLE 26 ¹H- Method NMR Retention LCMS Purity for Number PRODUCT Salt¹H-NMR Solvent LCMS Time Protocol percent Coupling 1679

HCl 1H NMR (300 MHz, DMSO) δ 10.36 (s, 1H), 9.65 (s, 1H), 9.13-8.99 (m,1H), 8.99-8.83 (m, 2H), 8.38 (d, J = 8.8 Hz, 1H), 8.30-8.16 (m, 1H),7.94- 7.80 (m, 1H), 7.55-7.35 (m, 3H), 7.09-6.97 (m, 1H), 4.16 (q, J =7.0 Hz, 2H), 3.31 (d, J = 4.3 Hz, 3H), 1.37 (t, J = 6.9 Hz, 3H). DMSO357 (M + 1) 1.62 Method D 100 Method AR/AS/ AT1 1680

1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.77 (d, J = 8.2 Hz, 1H),8.73-8.51 (m, 3H), 8.16 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H),7.60-7.32 (m, 4H), 7.01 (s, 1H), 4.21 (s, 2H), 3.70 (s, 2H), 3.33 (s,3H), 3.19 (s, 3H). DMSO 387 (M + 1) 1.49 Method D 100 Method AR/AS/ ATI1681

1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.78 (d, J = 7.9 Hz, 1H),8.72-8.49 (m, 3H), 8.22-8.01 (m, 2H), 7.85 (d, J = 8.6 Hz, 1H),7.62-7.36 (m, 4H), 7.01 (s, 1H), 4.59 (s, 2H), 3.19 (d, J = 4.0 Hz, 3H),2.68 (d, J = 4.5 Hz, 3H). DMSO 400 (M + 1) 1.31 Method D 100 Method AR/Wwith KI 1682

2HCl 1H NMR (300 MHz, DMSO) δ 10.47 (s, 1H), 9.65 (d, J = 1.7 Hz, 1H),9.05 (d, J = 7.9 Hz, 1H), 9.01- 8.88 (m, 2H), 8.39 (m, 1H), 8.23 (d, J =8.8 Hz, 1H), 7.87 (dd, J = 8.0, 5.3 Hz, 1H), 7.65-7.39 (m, 3H), 7.09 (m,1H), 6.44 (m, 1H), 4.47 (td, J = 14.7, 3.4 Hz, 2H), 3.29 (d, J = 4.5 Hz,3H). DMSO 393.4 (M + 1) Method C (NH4HCO3) 100 Method AR/AS (K2CO3, DMF-THF (1:1), 60° C.) then Method AT 1683

HCl ¹H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.60 (s, 1H), 9.03-8.87 (m,2H), 8.77 (s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.21-8.02 (m, 1H),7.92-7.69 (m, 3H), 7.20-7.02 (m, 2H), 4.93 (s, 2H), 3.70-3.40 (m, 8H),3.29 (d, J = 3.5 Hz, 3H). DMSO 456 (M + 1) 1.73 Method B (Ammoniumformate) 100 Method AR/W with KI 1684

HCl ¹H NMR (300 MHz, DMSO) δ 10.38 (s, 1H), 9.64 (s, 1H), 9.02 (d, J =6.7 Hz, 1H), 8.93 (d, J = 4.9 Hz, 1H), 8.84 (s, 1H), 8.34 (d, J = 9.0Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 7.98-7.70 (m, 3H), 7.11 (d, J = 7.3Hz, 2H), 4.26-4.05 (m, 2H), 3.78-3.57 (m, 2H), 3.45-3.19 (m, 6H). DMSO387 (M + 1) 1.47 Method A (Formic acid) 100 Method AR/AS/ AT1 1685

HCl ¹H NMR (300 MHz, DMSO) δ 11.31 (s, 1H), 10.41 (s, 1H), 9.63 (s, 1H),9.10-8.79 (m, 3H), 8.34 (d, J = 8.2 Hz, 1H), 8.28-8.12 (m, 1H), 7.92 (d,J = 8.0 Hz, 2H), 7.87-7.74 (m, 1H), 7.18 (d, J = 8.0 Hz, 2H), 4.60-4.46(m, 2H), 4.06-3.91 (m, 2H), 3.91- 3.74 (m, 2H), 3.67-3.41 (m, 4H),3.38-3.09 (m, J = 10.1 Hz, 5H). DMSO 442 (M + 1) 1.22 Method A (Formicacid) 100 Method AR/AS/ AT2 1686

HCl ¹H NMR (300 MHz, DMSO) δ 10.32-9.70 (m, 1H), 9.61 (s, 1H), 9.13-8.70(m, 5H), 8.29 (d, J = 8.5 Hz, 1H), 8.20-8.01 (m, 1H), 7.89 (d, J = 8.6Hz, 2H), 7.83-7.67 (m, 1H), 7.16 (d, J = 8.8 Hz, 2H), 4.38-4.27 (m, 2H),3.43-3.32 (m, 2H), 3.27 (d, J = 3.7 Hz, 3H), 2.63 (t, J = 4.8 Hz, 3H).DMSO 386 (M + 1) 1.46 Method B (Ammonium formate) 100 Method AR/AS/ AT21687

HCl ¹H NMR (300 MHz, DMSO) δ 9.95 (s, 1H), 9.62 (s, 1H), 9.13-8.86 (m, J= 5.2 Hz, 3H), 8.39 (d, J = 8.7 Hz, 1H), 8.26 (s, 1H), 7.97-7.80 (m,1H), 7.61- 7.37 (m, 3H), 7.14-6.98 (m, 1H), 5.01-4.81 (m, 1H), 4.31-4.13(m, 2H), 3.79-3.63 (m, 2H), 1.42 (d, J = 6.5 Hz, 6H). DMSO 415 (M + 1)1.65 Method A (Formic acid) 100 Method AR/AS/ AT1 1688

HCl ¹H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.63 (s, 1H), 9.10-8.88 (m,2H), 8.72 (s, 1H), 8.44 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H),7.85 (dd, J = 7.6, 4.8 Hz, 1H), 7.52 (d, J = 6.3 Hz, 1H), 7.39 (t, J =7.9 Hz, 1H), 7.22-7.04 (m, 2H), 4.97 (s, 2H), 3.30 (d, J = 4.1 Hz, 3H).2.97 (s, 3H), 2.85 (s, 3H). DMSO 414 (M + 1) 1.28 Method A (Formic acid)100 Method AR/W with KI 1689

HCl ¹H NMR (300 MHz, DMSO) δ 10.22 (s, 1H), 9.63 (s, 1H), 9.10-8.87 (m,2H), 8.75 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H),8.01 (d, J = 4.2 Hz, 1H), 7.93-7.77 (m, 1H), 7.51 (d, J = 7.3 Hz, 1H),7.43 (t, J = 7.8 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 8.5 Hz,1H), 4.54 (s, 2H), 3.29 (d, J = 3.9 Hz, 3H), 2.64 (d, J = 4.4 Hz, 3H).DMSO 400 (M + 1) 1.33 Method A (Formic acid) 100 Method AR/W with KI1690

HCl ¹H NMR (300 MHz, DMSO) δ 10.09 (s, 1H), 9.62 (s, 1H), 9.05-8.87 (m,2H), 8.60 (s, 1H), 8.26 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 3.8 Hz, 1H),7.90-7.77 (m, 1H), 7.54-7.36 (m, 2H), 7.26-7.06 (m, 2H), 4.23-4.11 (m,2H), 3.70-3.58 (m, 2H), 3.29 (d, J = 4.4 Hz, 3H), 3.24 (s, 3H). DMSO 387(M + 1) 1.51 Method A (Formic acid) 100 Method AR/AS/ AT1 1691

HCl ¹H NMR (300 MHz, DMSO) δ 9.65 (s, 1H), 9.04 (d, J = 7.8 Hz, 1H),8.94 (d, J = 5.0 Hz, 1H), 8.50 (s,1H), 8.39-8.22 (m, 2H), 7.97-7.80 (m,1H), 7.53-7.31 (m, 3H), 7.03 (d, J = 6.8 Hz, 1H), 4.26-4.13 (m, 2H),3.82-3.59 (m, 8H), 3.32 (s, 3H). DMSO 401 (M + 1) 1.47 Method A (Formicacid) 100 Method AR/AS/ AT1 1692

HCl ¹H NMR (300 MHz, DMS0) δ 9.83-9.26 (m, 3H), 9.00-8.76 (m, 3H), 8.40(d, J = 8.8 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.89-7.72 (m, 1H),7.58-7.36 (m, 3H), 7.04 (d, J = 3.4 Hz, 1H), 4.30-4.18 (m, 2H),3.79-3.66 (m, 2H), 3.33 (s, 3H). DMSO 373 (M + 1) 1.42 Method A (Formicacid) 100 Method AR/AS/ AT1 1693

HCl ¹H NMR (300 MHz, DMSO) δ 10.73-10.36 (m, 1H), 9.65 (s, 1H),9.13-8.98 (m, 2H), 8.93 (d, J = 5.0 Hz, 1H), 8.38 (d, J = 3.4 Hz, 1H),8.24 (d, J = 7.7 Hz, 1H), 7.94-7.75 (m, 1H), 7.69-7.41 (m, 3H), 7.09 (d,J = 8.1 Hz, 1H), 4.61-4.43 (m, 2H), 4.28- 4.07 (m, 2H), 3.59-3.39 (m,2H), 3.30 (d, J = 2.8 Hz, 3H). DMSO 454 (M + 1) 2.26 Method B (Ammoniumformate) 100 Method AR/AS/ AT3 1694

HCl ¹H NMR (300 MHz, DMSO) δ 10.35 (s, 1H), 9.67 (s, 1H), 9.04 (d, J =7.3 Hz, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.78 (s, 1H), 8.24 (s, 2H),7.96-7.77 (m, 1H), 7.60-7.40 (m, 2H), 7.33-7.10 (m, 2H), 4.50-4.36 (m,2H), 4.05-3.85 (m, 2H), 3.53-3.37 (m, 2H), 3.28 (d, J = 3.6 Hz, 3H),DMSO 454 (M + 1) 2.11 Method B (Ammonium formate) 100 Method AR/AS/ AT31695

¹H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H),8.73-8.50 (m, 3H), 8.14 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H),7.54 (dd, J = 7.9, 4.8 Hz, 1H), 7.48-7.34 (m, 3H), 6.96 (d, J = 3.2 Hz,1H), 4.91 (s, 2H), 3.18 (d, J = 4.3 Hz, 3H), 3.03 (s, 3H), 2.86 (s, 3H).DMSO 414 (M + 1) 1.30 Method A (Formic acid) 100 Method AR/W with KI

Method AV: 1-(Benzyloxy)-7-bromo-3-chloroisoquinoline (lxv-a)

To 20 mL of benzyalcohol was slowly added Na (2.00 g, 86.9 mmol) at 0°C., the mixture was then stirred at room temperature for 4 h.7-bromo-1,3-dichloroisoquinoline (2.00 g, 7.2 mmol) in toluene (50 mL)was added to the mixture with stirring. The reaction mixture was heatedat 80° C. overnight. The solvent was removed under reduced pressure, theresidue was purified with chromatography on silica gel (petroleum ether)to give 2.00 g xiv-a as a white solid (yield 80%) LCMS m/z=257.9, 259.9(M+1) (Method B) (retention time=1.62 min).

Method AQ1: 1-(Benzyloxy)-3-chloro-7-(3-methoxyphenyl)isoquinoline(lxvi-a)

To a mixture of 1-(benzyloxy)-7-bromo-3-chloroisoquinoline (1.00 g, 2.86mmol, 1.0 eq), 3-methoxyphenylboronic acid (435 mg, 2.86 mmol, 1.0 eq),K₂CO₃ (2.13 g, 15.4 mmol, 5.4 eq) in dioxane (10 mL) and H₂O (5 mL) wasadded Pd(PPh₃)₂Cl₂ (100 mg, 0.15 mmol, 0.05 eq) under N₂ atmosphere. Theresulting mixture was stirred at 110° C. under N₂ atmosphere overnight.The solvent was removed in vacuo and the residue was purified withchromatography on silica gel (hexane/ethyl acetate 250:1) to give 550 mgof lxvi-a as white solid (yield 37%). LCMS m/z=376.0 (M+1) (Method B)(retention time=2.43 min).

Method AQ3:1-(Benzyloxy)-7-(3-methoxyphenyl)-3-(pyridin-3-yl)isoquinoline (lxvii-a)

To a mixture of 1-(benzyloxy)-3-chloro-7-(3-methoxyphenyl)isoquinoline(150 mg, 0.40 mmol, 1.0 eq), pyridin-3-ylboronic acid (74 mg, 0.60 mmol,1.5 eq), K₂CO₃ (166 mg, 1.20 mmol, 3.0 eq) in dioxane (2 ml) and H₂O (1mL) was added Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol, 0.05 eq) under N₂atmosphere. The sealed tube was irradiated in the CEM microwave at 130°C. for 1 h. After the reaction was completed, the volatiles were removedin vacuo and the residue was purified with chromatography on silica gel(hexane/ethyl acetate 50:1) to give 200 mg of crude lxvii-a as a brownoil, which was used directly in the next step without purification, LCMSm/z=419.0 (M+1) (Method B) (retention time=2.25 min).

Method AW: 7-(3-Methoxyphenyl)-3-(pyridin-3-yl)isoquinolin-1-ol(lxviii-a)

A mixture of1-(benzyloxy)-7-(3-methoxyphenyl)-3-(pyridin-3-yl)isoquinoline (200 mg,0.48 mmol), and concentrated HCl (10 mL) in ethanol (20 mL) was stirredat room temperature overnight. After the reaction was completed, themixture was filtered and concentrated to afford 130 mg of lxviii-a as ayellow solid (yield 90% for two steps). LCMS m/z=329.0 (M+1) (Method B)(retention time=1.66 min).

Method AX: 1-Chloro-7-(3-methoxyphenyl)-3-(pyridin-3-yl)isoquinoline(lxix-a)

To a mixture of 7-(3-methoxyphenyl)-3-(pyridin-3-yl)isoquinolin-1-ol(130 mg, 0.395 mmol) in phenylphosphonic dichloride (5 mL) was stirredat 120° C. overnight. After the reaction was completed, the mixture wasadded to ice-water slowly. The pH was adjusted to 7 by slow addition ofNH₃H₂O at 0° C. Then the mixture was extracted with dichloromethane (100mL×3). The combined organic layer were dried over MgSO₄, filtered andconcentrated in vacuo to give 130 mg of crude lxix-a as a white solid,which was used directly in the next step without purification. LCMSm/z=346.9 (M+1) (Method B) (retention time=1.80 min).

Method AY:7-(3-Methoxyphenyl)-N-methyl-3-(pyridin-3-yl)isoquinolin-1-amine (lxx-a)

A mixture of 1-chloro-7-(3-methoxyphenyl)-3-(pyridin-3-yl)isoquinoline(90 mg, 0.26 mmol), methylamine hydrochloride (200 mg, 2.96 mmol, 10.0eq) and Et₃N (0.5 mL) was added to a sealed tube with i-AmOH (2 mL). Thesealed tube was irradiated in the CEM microwave at 160° C. for 1 h.After the reaction was completed, the i-AmOH was removed in vacuo andthe residue was dissolved in 10 mL of water and dichloromethane, themixture was extracted with dichloromethane (3×50 mL). The combinedorganic layers were dried over MgSO₄, filtered and concentrated in vacuoand the residue was washed with MeOH to give 5 mg of lxx-a as a brownsolid (yield 6%). LCMS m/z=342.1 (M+1) (Method B) (retention time=2.02min). ¹H NMR (400 MHz, DMSO-d₆): δ 9.40 (d, J=0.9 Hz, 1H), 8.67-8.47 (m,3H), 8.08-7.95 (m, 1H), 7.89-7.84 (m, 2H), 7.66 (s, 1H), 7.57-7.49 (m,1H), 7.46-7.42 (m, 3H), 7.08-6.95 (m, 1H), 3.88 (s, 3H), 3.14 (d, J=4.3Hz, 3H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 81, replacing with the appropriateisoquinoline and aniline.

TABLE 27 Molec- ¹H- Method Num- Salt ular NMR LCMS Purity for berPRODUCT type Mass ¹H-NMR Solvent LCMS Protocol percent Coupling 1697

341.41 1H-NMR (400 MHz, DMSO-d6): δ 9.40 (d, J = 0.9 Hz, 1H), 8.67- 8.47(m, 3H), 8.08- 7.95 (m, 1H), 7.89- 7.84 (m, 2H), 7.66 (s, 1H), 7.57-7.49(m, 1H), 7.46-7.42 (m, 3H), 7.08-6.95 (m, 1H), 3.88 (s, 3H), 3.14 (d, J= 4.3 Hz, 3H). DMSO 342.1 (M + 1) Method B (NH4HCO3) 95 Method AX, H11698

312.37 1H-NMR (400 MHz, DMSO-d6): δ 9.40 (d, J = 1.8 Hz, 1H), 9.12 (d, J= 2.1 Hz, 1H), 8.66 (s, 1H), 8.60 (m, 2H), 8.54 (dt, J = 8.0, 1.9 Hz,1H), 8.29-8.23 (m, 1H), 8.08 (dd, J = 8.5, 1.6 Hz, 1H), 7.92 (d, J = 8.5Hz, 1H), 7.87 (d, J = 4.5 Hz, 1H), 7.68 (s, 1H), 7.56 (dd, J = 7.8, 4.8Hz, 1H), 7.51 (dd, J = 7.8, 4.8 Hz, 1H), 3.14 (d, J = 4.4 Hz, 3H). DMSO312.9 ( M + 1) Method B (NH4HCO3) 95 Method AX, H1

Method BA: Synthesis of5-[3-(4-Methylamino-2-pyridin-3-yl-quinazolin-6-yl)-phenoxymethyl]-oxazolidin-2-one(lxxi-a)

To 5-(chloromethyl)oxazolidin-2-one (45 μmol) was added the solution of3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol (30 μmol) inNMP (200 μL). PS-BEMP (90 μmol) was added to the vials by resindispenser. After the reaction mixture was heated at 90° C. for 12 h, theresidue was diluted with methanol and purified by PREP-HPLC Condition D.The target fraction was lyophilized to afford the titled compound whosestructure was finally confirmed by LCMS using LCMS Method E.

The compounds in the following table were prepared in a manner analogousto that described in Scheme 80, replacing5-(chloromethyl)oxazolidin-2-one with the appropriate alkyl halide.

TABLE 28 Starting Starting Number Material 1 Material 2 1699

1700

1701

1702

1703

1704

1705

1706

1707

1708

1709

1710

1711

1712

1713

1714

1715

Number Product 1699

1700

1701

1702

1703

1704

1705

1706

1707

1708

1709

1710

1711

1712

1713

1714

1715

Exact Mass Found Number Salt Type Mass (M + 1) Purity (%) 1699 427 42898 1700 421 422 98 1701 TFA 467 468 98 1702 515 516 98 1703 2TFA 468 46998 1704 TFA 436 437 98 1705 455 456 98 1706 438 439 98 1707 421 422 981708 453 454 98 1709 TFA 467 468 98 1710 487 488 98 1711 TFA 515 516 981712 TFA 436 437 98 1713 TFA 422 423 98 1714 TFA 476 477 98 1715 2TFA438 439 98

Method BB: Synthesis of3-methyl-6-((3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin6-yl)phenoxy)methyl)benzo[d]oxazol-2(3H)-one (lxxi-b)

To 6-(hydroxymethyl)-3-methylbenzo[d]oxazol-2(3H)-one (45.1 μmol) wasadded the solution of3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol (30 μmol) inTHF (400 μL). After PS-triphenylphosphine (60 μmol) was added, thesolution of DBAD (di-tert-butyl azodicarboxylate, 66 mmol) in THF wasdispensed to the vials. The mixture was heated at 50° C. for 8 h. Afterthe solvent was removed, the residue was diluted with methanol andpurified by Mass triggered PREP-HPLC Condition D. The target fractionwas lyophilized to afford the titled compound whose structure wasfinally confirmed by LCMS using LCMS Method E.

The compounds in the following table were prepared in a manner analogousto that described in Scheme 85, replacing6-(hydroxymethyl)-3-methylbenzo[d]oxazol-2(3H)-one with the appropriatealkyl alcohol.

TABLE 29 Starting Starting Number Material 1 Material 2 1716

1717

1718

1719

1720

1721

1722

1723

1724

1725

1726

1727

1728

1729

1730

1731

1732

1733

1734

1735

1736

1737

1738

Number Product 1716

1717

1718

1719

1720

1721

1722

1723

1724

1725

1726

1727

1728

1729

1730

1731

1732

1733

1734

1735

1736

1737

1738

Mass Salt Exact Found Number Type Mass (M + 1) Purity (%) 1716 TFA 489490 100 1717 TFA 448 449 100 1718 TFA 422 423 100 1719 TFA 422 423 1001720 TFA 472 473 100 1721 TFA 489 490 100 1722 TFA 489 490 100 1723 TFA466 467 100 1724 TFA 425 426  94 1725 TFA 453 454 100 1726 TFA 489 490100 1727 TFA 489 490 100 1728 TFA 448 449 100 1729 TFA 422 423 100 1730TFA 504 505 100 1731 TFA 424 425 100 1732 TFA 433 434 100 1733 TFA 484485 100 1734 TFA 466 467 100 1735 TFA 425 426 100 1736 TFA 464 465  951737 TFA 466 467 100 1738 TFA 489 490 100

Synthesis of N-(6-bromo-2-(pyridin-3-yl)quinazolin-4-yl)acetamide(lxxii-a)

A 100 mL round bottom flask was fitted with a reflux condenser andcharged with 6-bromo-2-(pyridin-3-yl)quinazolin-4-amine (2.45 g, 8.14mmol), acetic anhydride (5.81 g, 57.0 mmol) and acetic acid (30 mL). Thereaction mixture was stirred at 90° C. for 20 min and then cooled toroom temperature. A precipitate formed during the reaction and wascollected by filtration and washed with water (100 mL). The solid wasdried at 60° C. to giveN-(6-bromo-2-(pyridin-3-yl)quinazolin-4-yl)acetamide as a white powder(1.83 g, 66%). ¹H NMR (300 MHz, CDCl₃) δ 9.72 (s, 1H), 8.84-8.69 (m,3H), 8.22 (s, 1H), 8.02-7.90 (m, 2H), 7.53-7.41 (m, 1H), 2.83 (s, 3H).

Synthesis ofN-(6-bromo-2-(pyridin-3-yl)quinazolin-4-yl)-N-methylacetamide (lxxiii-a)

To a solution of 6-bromo-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine(1.20 g, 3.81 mmol) in acetic acid (10 mL) was added acetic anhydride(1.94 g, 19.0 mmol) and stirred at 195° C. using microwave for 6 h. Thereaction mixture was checked by LC-MS, no starting material wasobserved, ice was added into the reaction. The precipitate was collectedby filtration and washed with water. The product was dried at 60° C. togive N-(6-bromo-2-(pyridin-3-yl)quinazolin-4-yl)-N-methylacetamide (711mg, 52%) as a light brown powder. ¹H NMR (300 MHz, CDCl₃) δ 9.76 (dd,J=2.2, 0.8 Hz, 1H), 8.85-8.79 (m, 1H), 8.76 (dd, J=4.8, 1.7 Hz, 1H),8.09 (dd, J=1.8, 0.8 Hz, 1H), 8.05-8.01 (m, 2H), 7.46 (ddd, J=8.0, 4.8,0.8 Hz, 1H), 3.52 (s, 3H), 2.11 (s, 3H).

Method BC: Synthesis of6-(2,3-difluorophenyl)-N-(3-methoxypropyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-aminedihydrochloride (lxxv-a) (Compound 1742)

To a solution of the hydroxyl derivative (520 mg, 1.27 mmol) in DMF (20mL) was added methyl iodide (262 mg, 1.84 mmol) and NaH (55% in oil; 69mg, 1.9 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 1 h and the ice water was added into the reactionmixture. The resulting solution was extracted with ethyl acetate (3times), dried over Na₂SO₄, concentrated and purified by columnchromatography (NH-silica gel, 50% hexane/50% ethyl acetate). Theresulting product was dissolved in isopropyl alcohol and 1N—HCl (5 mL)was added and a precipitate formed which was collected by filtration anddried at 60° C. to give6-(2,3-difluorophenyl)-N-(3-methoxypropyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-aminedihydrochloride as an orange powder (130 mg, 21%). ¹H NMR (300 MHz,DMSO) δ 9.66 (d, J=1.6 Hz, 1H), 9.09 (d, J=8.1 Hz, 1H), 8.96 (dd, J=5.1,1.5 Hz, 1H), 8.51 (s, 1H), 8.33 (d, J=8.7 Hz, 1H), 8.20 (d, J=8.8 z,1H), 7.90 (dd, J=8.1, 5.1 Hz, 1H), 7.66-7.47 (m, 2H), 7.47-7.32 (m, 1H),4.22-4.07 (m, 2H), 3.70 (s, 3H), 3.48 (t, J=5.8 Hz, 2H), 3.22 (s, 3H),2.19-2.01 (m, 2H).

Method BD:2-(3-(4-(dimethylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenyl)ethanol,2HCl (lxxvi-a)

To a reaction vial containing2-(3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenyl)ethanol(89.0 mg, 0.25 mmol) in DMF (1 ml) was added 60% sodium hydride (13 mg,0.325 mmol) and iodomethane (0.02 mL, 0.325 mmol). The reaction mixturewas allowed to stir at ambient temperature for 12 h. Water (20 ml) wasadded to the reaction mixture, and the crude product was extracted withethyl acetate (4×15 mL). The crude material was purified via ISCO(silica, 4 g column, 95% CH₂Cl₂-5% MeOH-0.1% NH₄OH) to give the productas an off-white solid. The free base was then converted to the HCl saltto yield the final product as a yellow solid (24.6 mg, 0.055 mmol, 22%).LC-MS m/z=371.5 (M+1) (retention time=1.86) ¹H NMR (300 MHz, DMSO) δ9.61 (d, J=211 Hz, 1H), 8.99 (d, J=7.5 Hz, 1H), 8.93 (dd, J=5.0, 1.5 Hz,1H), 8.48 (d, J=1.0 Hz, 1H), 8.28 (dd, J=17.4, 9.4 Hz, 2H), 7.84 (dd,J=7.7, 5.1 Hz, 1H), 7.69-7.60 (m, 2H), 7.44 (t, J=7.5 Hz, 1H), 7.30 (d,J=7.3 Hz, 1H), 3.78-3.61 (m, 9H), 2.82 (t, J=7.0 Hz, 2H).

Synthesis of6-(2,4-difluorophenyl)-N-(3-methoxypropyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-aminedihydrochloride (lxxvii-a) (Compound 1744)

6-(2,4-difluorophenyl)-N-(3-methoxypropyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-aminedihydrochloride was synthesized in a similar manner to that describedfor6-(2,3-difluorophenyl)-N-(3-methoxypropyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-aminedihydrochloride substituting the appropriate hydroxyl derivative.6-(2,4-difluorophenyl)-N-(3-methoxypropyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-aminewas obtained as the dihydrochloride salt ¹H NMR (300 MHz, DMSO) δ 9.69(d, J=2.0 Hz, 1H), 9.14 (d, J=8.3 Hz, 1H), 8.97 (dd, J=5.1, 1.2 Hz, 1H),8.45 (s, 1H), 8.39 (d, J=8.6 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.92 (dd,J=8.0, 5.2 Hz, 1H), 7.86-7.73 (m, 1H), 7.57-7.38 (m, 1H), 7.36-7.23 (m,1H), 4.19-4.04 (m, 2H), 3.71 (s, 3H), 3.48 (t, J=5.7 Hz, 2H), 3.23 (s,3H), 2.21-1.96 (m, 2H).

Method BE:4-(3,4-dichlorophenyl)-1-(6-(3-methoxyphenyl)-2-(pyridin-3-yl)quinazolin-4-yl)pyrrolidin-2-one(lxxviii-a)

To a mixture of 4-chloro-6-(3-methoxyphenyl)-2-(pyridin-3-yl)quinazoline(40 mg, 0.12 mmol), 4-(3,4-dichlorophenyl)pyrrolidin-2-one (100 mg,0.437 mmol) and Cs₂CO₃ (42 mg, 0.127 mmol) in dry toluene (6 mL) wasadded Pd(OAc)₂ (3 mg, 0.01 mmol) and Xantphos (10 mg, 0.02 mmol) under anitrogen atmosphere. The resulting mixture was stirred at 100° C. for 12h. After cooling, the mixture was filtered through a pad of celite. Theresidue was purified by silica gel chromatography, eluted with petroleumether/ethyl acetate (5:4) to give the desired product as a yellow solid.14 mg of the desired product was obtained in a 22.5% yield, LCMS:retention time=1.802 min, [MH]⁺=541.0, 543.0. ¹H-NMR (400 MHz, DMSO-d₆):δ 9.73 (s, 1H), 9.05-9.04 (m, 1H), 8.86-8.85 (m, 1H), 8.42-8.38 (m, 2H),8.19 (d, J=8.8 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.82-7.81 (m, 1H), 7.69(d, J=8.0 Hz, 1H), 7.58 (dd, J=8.0, 1.6 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H),7.41-7.36 (m, 2H), 7.07 (dd, J=8.0, 2.0 Hz, 1H), 4.57-4.46 (m, 2H),4.06-4.03 (m, 1H), 3.20-3.01 (m, 2H), 3.88 (s, 3H).

The compounds in the following table were prepared in a manner analogousto that described in Scheme 91, replacing4-(3,4-dichlorophenyl)pyrrolidin-2-one with the appropriate amide

TABLE 30 ¹H NMR Purity Method LCMS Number Product Salt type ¹H NMRSolvent percent of Coupling LCMS Method 1745

¹H-NMR (400 MHz, DMSO-d₆): δ 9.75 (s, 1H), 8.90 (d, J = 8.0 Hz, 1H),8.78 (d, J = 4.0 Hz, 1H), 8.35 (s, 1H), 8.28-8.19 (m, 2H), 7.92 (d, J =7.6 Hz, 1H), 7.82 (d, J = 5.0 Hz, 2H), 7.73-7.70 (m, 1H), 7.68-7.61 (m,2H), 7.52- 7.42 (m, 1H), 7.29 (t, J = 8.4 Hz, 1H), 5.61 (s, 2H). DMSO 95Method BE 451.0 (M + 1) Method B (NH₄HCO₃) 1746

¹H-NMR (400 MHz, DMSO-d₆): δ 9.74 (s, 1H), 8.89 (d, J = 8.0 Hz, 1H),8.77 (d, J = 3.8 Hz, 1H), 8.45 (s, 1H), 8.39 (d, J = 8.7 Hz, 1H), 8.18(d, J = 8.7 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.83 (s, 2H), 7.72-7.56(m, 2H), 7.52- 7.27 (m, 3H), 7.03 (d, J = 7.9 Hz, 1H), 5.60 (s, 2H),3.85 (s, 3H). DMSO 95 Method BE 445.1 (M + 1) Method B (NH₄HCO₃) 1747

¹H-NMR (400 MHz, DMSO-d₆): δ 9.76 (s, 1H), 8.91 (d, J = 6.4 Hz, 1H),8.79 (s, 1H), 8.41 (s, 1H), 8.30-8.23 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H),7.83 (s, 2H), 7.65 (d, J = 3.6 Hz, 2H), 7.55-7.49 (m, 2H), 7.40 (s, 1H),5.61 (s, 2H). DMSO 95 Method BE 451.0, 452.0, (M + 1) Method B (NH₄HCO₃)1748

2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 9.73 (s, 1H), 9.05-9.04 (m, 1H),8.36-8.85 (m, 1H), 8.42- 8.38 (m, 2H), 8.19 (d, J = 8.8 Hz, 1H), 7.89(d, J = 1.6 Hz, 1H), 7.82-7.81 (m, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.58(dd, J = 8.0, 1.6 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.41-7.36 (m, 2H),7.07 (dd, J = 8.0, 2.0 Hz, 1H), 4.57-4.46 (m, 2H), 4.06-4.03 (m, 1H),3.20-3.01 (m, 2H), 3.88 (s, 3H), DMSO 95 Method BE 541.0, 543.0 (M + 1)Method B (NH₄HCO₃) 1749

2HCl ¹H-NMR (400 MHz, DMSO-d₆): δ 9.68 (s, 1H), 8.83 (d, J = 8.0 Hz,1H), 8.76 (s, 1H), 8.39- 8.37 (m, 2H), 8.17 (d, J = 10.0 Hz, 1H), 7.63-7.31 (m, 9H), 7.06 (dd, J = 8.4, 2.0 Hz, 1H), 4.56-4.45 (m, 2H),4.03-3.99 (m, 1H), 3.88 (s, 3H), 3.19-2.97 (m, 2H). DMSO 95 Method BE472.9 (M + 1) Method B (NH₄HCO₃) 1750

¹H-NMR (400 MHz, DMSO-d₆): δ 9.74 (d, J = 8.4 Hz, 1H), 8.89 (dt, J =8.4, 1.6 Hz, 1H), 8.78 (dd, J = 4.4,1.2 Hz, 1H), 8.46 (d, J = 1.6 Hz,1H), 8.41. (dd, J = 8.8, 1.6 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.97 (s,1H), 7.88 (s, 2H), 7.65-7.62 (m, 1H), 7.48-7.44 (m, 1H),7.41-7.37 (m,2H), 7.04 (dd, J = 8.0, 1.6 Hz, 1H), 5.59 (s, 2H), 3.86 (s, 3H). DMSO 95Method BE 479.0 (M + 1) Method B (NH₄HCO₃) 1751

¹H-NMR (400 MHz, DMSO-d₆): δ 9.74 (s, 1H), 8.89 (d, J = 8.4 Hz, 1H),8.78 (d, J = 4.4 Hz, 1H), 8.46 (s, 1H), 8.41 (d, J = 9.2 Hz, 1H), 8.20(d, J = 8.8 Hz, 1H), 7.91-7.87 (m, 1H), 7.77-7.62 (m, 3H), 7.48-7.37 (m,3H), 7.03 (d, J = 6.4 Hz, 1H), 5.58 (s, 2H), 3.86 (s, 3H). DMSO 95Method BE 463.1 (M + 1) Method B (NH₄HCO₃)

N-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine(1.51 g, 3.87 mmol) was dissolved in CH₂Cl₂/MeOH (20 mL/20 mL).Methanesulfonic acid (0.251 mL, 3.87 mmol) was added to the solution.The volatiles were evaporated in vacuo. The resultant residue wascrystallized from EtOH (30 mL) to give 1.35 g ofN-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-aminemethanesulfonate as a light yellow powder (72%), LCMS m/z=391 (M+1)(Method D) (Retention time=1.91 min). ¹H NMR (300 MHz, DMSO) δ 9.52 (s,1H), 9.01-8.83 (m, 2H), 8.75 (s, 1H), 8.58 (s, 1H), 8.09 (d, J=7.2 Hz,1H), 8.03-7.85 (m, 2H), 7.83-7.68 (m, 1H), 7.59-7.43 (m, 1H), 7.33 (t,J=7.91 Hz, 1H), 2.31 (s, 3H), 1.66 (s, 9H).

N-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine(1.22 g, 3.12 mmol) was dissolved in CH₂Cl₂ 1/MeOH (20 mL/20 mL).Fumaric acid (0.363 g, 3.12 mmol) was added to the solution. The mixturewas sonicated until fumaric acid was dissolved. Then, the volatiles wereevaporated in vacuo. The resultant solid was washed with MeOH and driedto give 1.28 g ofN-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine ½fumarate as a light yellow powder (91%). LCMS m/z=391 (M+1) (Method D)(Retention time=1.95 min). ¹H NMR (300 MHz, DMSO) δ 13.14 (s, 1H), 9.59(s, 1H), 8.82-8.65 (m, 2H), 8.57 (s, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.82(d, J=8.7 Hz, 1H), 7.79-7.62 (m, 2H), 7.61-7.52 (m, 1H), 7.51-7.38 (m,1H), 7.28 (t, J=8.61 Hz, 1H), 6.61 (s, 1H), 1.64 (s, 9H).

N-methyl-6-(3-(2-propoxyethoxy)phenyl)-2-(pyridin-3-yl)quinazolin-4-aminefumarate was synthesized in a similar manner to that describedN-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-aminefumarate. LCMS m/z=415.5 (M+1) (Method C(NH₄HCO₃) (Retention time=2.43min). ¹H NMR (300 MHz, CD₃OD) δ 9.57 (s, 1H), 8.84 (m, 1H), 8.63 (s,1H), 8.35 (m, 1H), 8.07 (m, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.58 (m, 1H),7.48-7.24 (m, 4H), 7.00 (m, 1H), 6.74 (s, 1H), 4.36-4.05 (m, 2H),4.00-3.70 (m, 2H), 3.53 (t, J=6.6 Hz, 2H), 3.29-3.13 (m, 3H), 1.75-1.51(m, 2H), 0.95 (t, J=7.4 Hz, 3H).

N-methyl-6-(3-(2-propoxyethoxy)phenyl)-2-(pyridin-3-yl)quinazolin-4-aminemethanesulfonate was synthesized in a similar manner to that describedN-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-aminemethanesulfonate. LCMS m/z=415.5 (M+1) (Method C(NH₄HCO₃) (Retentiontime=2.43 min). ¹H NMR (300 MHz, CD₃OD) δ 9.49 (s, 1H), 9.00-8.72 (m,1H), 8.53 (s, 1H), 8.29 (m, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.80 (dd,J=8.0, 5.1 Hz, 1H), 7.52-7.25 (m, 3H), 7.02 (m, 1H), 4.38-4.06 (m, 2H),3.98-3.72 (m, 2H), 3.61-3.48 (m, 2H), 3.42 (d, J=0.6 Hz, 3H), 3.34-3.26(m, 2H), 2.71 (s, 3H), 1.80-1.47 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).

Biological Testing:

STEP46 Biochemical Assays

Serial dilutions of compounds were performed in 100% DMSO and 1 uL ofcompounds were dispensed into 384-well black polystyrene plates(Corning, N.Y.). Compounds were incubated with 24 uL of buffercontaining 50 mM Hepes, 1 mM DTT, 0.02% Brij35, 1 ng/well purifiedSTEP46 enzyme for 30 nm in at room temperature. The reaction wasinitiated by addition of 25 uL of DiFMUP(6,8-difluoro-4-methylumbelliferyl phosphate) (InVitrogen, CA) with afinal concentration of 10 μM and incubated at 27° C. for 90 min. FinalDMSO concentration is 2%. Plates were read with florescence intensity atexcitation/emission of 360/460 nm using a PheraStar plate reader (BMGLabtech, NC).

Data Analysis

Data were expressed as percentage (%) inhibition of enzyme activity. 0%inhibition is defined as the RFUs (relative fluorescence units) in theabsence of compounds and 100% inhibition is defined as RFUs in theabsence of STEP46 enzyme. IC₅₀ values of compounds with inhibitoryactivity against STEP46 were determined by GraphPad Prism (version 4.03)using four parameter logistic equation. Some compounds act asactivators. For compounds showing STEP46 enzymatic activation, data arerepresented as percentage of inhibition but with negative values atthree representative concentrations (25, 50 and 100 uM).

Compounds 1-1760 show either inhibition or activation>50% at 100 uM, 50or 25 uM.

STEP IC50 Number (μM) 73 ++ 296 ++ 297 + 300 + 303 ++ 306 + 309 ++ 312+++ 313 +++ 314 ++ 315 ++ 316 +++ 317 ++ 318 ++ 320 ++ 322 + 325 +++ 326++ 327 ++ 329 +++ 330 ++ 332 +++ 333 +++ 334 ++ 335 +++ 336 +++ 337 +++339 ++ 341 ++ 342 ++ 343 + 344 ++ 346 ++ 348 ++ 352 ++ 390 ++ 391 ++ 392++ 393 ++ 396 ++ 399 +++ 400 ++ 403 ++ 407 ++ 412 +++ 415 ++ 416 +++ 418++ 419 +++ 421 + 423 ++ 424 ++ 425 ++ 426 + 427 ++ 428 ++ 429 +++ 430+++ 431 +++ 433 ++ 434 ++ 435 +++ 436 ++ 437 ++ 439 +++ 440 ++ 441 ++442 +++ 443 +++ 444 +++ 445 +++ 446 ++ 447 ++ 448 +++ 449 ++ 451 +++ 452+++ 453 +++ 454 ++ 455 ++ 456 +++ 457 ++ 458 +++ 459 +++ 460 ++ 461 ++463 ++ 466 ++ 467 ++ 468 +++ 470 ++ 471 ++ 472 ++ 473 ++ 474 ++ 629 ++630 ++ 631 ++ 632 +++ 633 ++ 634 ++ 635 +++ 636 + 637 ++ 638 ++ 639 +++640 ++ 641 +++ 642 +++ 643 +++ 644 ++ 645 ++ 647 ++ 648 ++ 649 ++ 650+++ 651 +++ 652 +++ 653 +++ 655 +++ 656 +++ 657 +++ 658 ++ 660 +++ 661+++ 662 +++ 663 +++ 664 ++ 665 ++ 666 +++ 667 +++ 668 +++ 669 +++ 670+++ 671 ++ 672 ++ 673 ++ 674 ++ 675 +++ 676 +++ 677 + 678 ++ 679 +++ 680++ 681 ++ 682 ++ 683 ++ 684 ++ 685 +++ 686 +++ 687 +++ 688 +++ 689 +++690 ++ 691 +++ 692 +++ 693 +++ 694 +++ 695 +++ 696 +++ 697 ++ 698 +++699 +++ 700 +++ 701 ++ 702 +++ 703 +++ 704 +++ 705 +++ 706 +++ 707 +++708 ++ 709 +++ 846 ++ 847 +++ 884 + 888 + 889 ++ 896 + 899 ++ 900 ++ 901++ 923 ++ 932 ++ 933 ++ 934 +++ 962 +++ 1124 +++ 1125 ++ 1126 ++ 1140+++ 1141 +++ 1142 ++ 1143 ++ 1144 ++ 1145 ++ 1146 ++ 1148 ++ 1150 + 1151++ 1152 ++ 1153 ++ 1155 ++ 1157 ++ 1158 ++ 1159 ++ 1160 ++ 1161 ++ 1165+++ 1167 ++ 1168 ++ 1171 ++ 1172 ++ 1173 + 1176 ++ 1178 ++ 1180 ++ 1181++ 1182 ++ 1183 ++ 1184 ++ 1185 ++ 1186 ++ 1187 +++ 1188 ++ 1191 ++ 1192++ 1193 ++ 1194 +++ 1198 ++ 1200 ++ 1201 ++ 1202 ++ 1203 ++ 1204 + 1205++ 1206 ++ 1208 + 1211 + 1212 ++ 1213 ++ 1214 ++ 1215 +++ 1216 +++ 1217++ 1218 ++ 1219 ++ 1220 + 1221 + 1222 ++ 1223 +++ 1225 ++ 1226 ++ 1227++ 1228 ++ 1229 ++ 1230 ++ 1234 ++ 1237 ++ 1238 ++ 1239 ++ 1248 ++ 1279++ 1280 ++ 1281 +++ 1282 ++ 1283 + 1284 ++ 1285 + 1286 ++ 1324 ++ 1327 +1328 + 1330 + 1332 ++ 1333 + 1334 + 1335 ++ 1336 ++ 1337 ++ 1339 ++ 1340++ 1341 ++ 1346 ++ 1348 + 1350 ++ 1351 ++ 1352 + 1353 ++ 1354 ++ 1356 ++1357 ++ 1358 ++ 1359 ++ 1360 ++ 1361 + 1362 ++ 1363 ++ 1364 ++ 1365 ++1366 ++ 1369 ++ 1370 ++ 1371 ++ 1372 ++ 1373 ++ 1374 ++ 1375 ++ 1376 ++1380 ++ 1381 ++ 1382 +++ 1391 + 1395 ++ 1396 ++ 1400 ++ 1401 ++ 1402 ++1403 + 1404 + 1406 ++ 1407 ++ 1408 ++ 1409 ++ 1410 ++ 1411 + 1412 ++1413 ++ 1414 ++ 1415 + 1416 ++ 1419 ++ 1420 ++ 1422 ++ 1423 + 1424 +1425 ++ 1430 ++ 1437 ++ 1445 ++ 1446 ++ 1447 + 1448 ++ 1449 + 1450 ++1451 ++ 1452 +++ 1453 ++ 1454 + 1455 ++ 1456 ++ 1458 + 1467 ++ 1497 ++1516 + 1601 ++ 1611 ++ 1680 ++ Key + IC₅₀ > 10 uM ++ IC₅₀ 1-10 uM +++IC₅₀ < 1 uM

Having thus described several aspects of at least one embodiment of thisinvention, it is to be appreciated various alterations, modifications,and improvements will readily occur to those skilled in the art. Suchalterations, modifications, and improvements are intended to be part ofthis disclosure, and are intended to be within the spirit and scope ofthe invention. Accordingly, the foregoing description and drawings areby way of example only.

What is claimed is:
 1. A compound of formula (I):

or a salt thereof, wherein: A is CH or N; B is phenyl, dihydroindenyl,dihydrobenzoxazinyl, dihydrobenzodioxinyl, chromenyl,tetrahydroisoquinolyl, tetrahydroquinolinyl, dihydroquinolyl, quinolyl,tetrahydroquinazolinyl, indolinyl, dihydrobenzothiazolyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, isoindolinyl, benzofuryl,benzothienyl, benzodioxolyl, indolyl, indazolyl, benzoimidazolyl,benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzoxadiazolyl, tetrahydrobenzothienyl, thienyl, thiazolyl, imidazolyl,pyrazolyl, thiadiazolyl or pyridyl; m is 0, 1, 2, 3, or 4; E is phenyl,thienyl, or pyrrolyl; when E is phenyl, n is 1 or 2; and when E isthienyl or pyrrolyl, n is 0 or 1; L is NR⁵; one of X and Z is N and theother is CH; p is 0, 1, or 2; each R¹ is independently C₁-C₈ alkyl,halo, haloalkyl, haloalkoxy, alkoxyalkyl, —CN, oxo, —NO₂,—C(Y)NR^(b)R^(b′), —NR^(c)C(Y)R^(c′), —SO₂NR^(b)R^(b′), —OR^(d), or—S(O)_(q)R^(f); each R² is independently C₁-C₈ alkyl, C₃-C₈ cycloalkyl,thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, —CN, —NO₂, —C(O)OR^(a),—C(Y)NR^(b)R^(b′), —NR^(b)R^(b′), —OR^(d), —C(Y)R^(e) or —S(O)_(q)R^(f);each R³ is independently C₁-C₈ alkyl, halo, haloalkyl, —NR^(b)R^(b′) or—OR^(d); R⁵ is hydrogen; or when m is not 0, R⁵ and one R¹ may be takentogether with the atoms to which they are attached to form an optionallysubstituted heteroaryl or heterocyclyl ring; Y is O or S; q is 1 or 2;and each R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(e), and R^(f) isindependently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈cycloalkyl, phenyl, dihydroindenyl, morpholinyl, tetrahydropyranyl,piperidyl, pyrrolidinyl, thiomorpholinyl, phenylalkyl, thienylalkyl,pyridylalkyl, tetrahydropyranylalkyl, dihydroindenylalkyl,tetrahydrofurylalkyl, hydroxyalkyl, morpholinylalkyl, pyrrolidinylalkyl,dialkylaminoalkyl, piperidylalkyl, benzodioxolilalkyl,dihydrobenzodioxinylalkyl, C₃-C₈ cycloalkylalkyl, haloalkyl oralkoxyalkyl.
 2. The compound according to claim 1 or a salt thereof,wherein: A is N; B is phenyl or pyridyl; m is 1, 2 or 3; E is phenyl; nis 1 or 2; p is 0 or 1; and R⁵ is hydrogen.
 3. The compound according toclaim 2 or a salt thereof, wherein: m is 1 or 2; p is 0; R¹ is C₁-C₈alkyl, halo, haloalkyl, haloalkoxy, —CN, —NO₂, —C(Y)NR^(b)R^(b′),—NR^(c)C(Y)R^(c′), —SO₂NR^(b)R^(b′), —OR^(d), or —S(O)_(q)R^(f); and R²is —OR^(d).
 4. The compound according to claim 3 or a salt thereof,wherein: R² is —OR^(d), in which R^(d) is C₁-C₈ alkyl; and each R^(b),R^(b′), R^(c), R^(c′), R^(d) and R^(f) is independently hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, phenyl,dihydroindenyl, tetrahydropyranyl, phenylalkyl, thienylalkyl,tetrahydropyranylalkyl, dihydroindenylalkyl, or haloalkyl.
 5. Thecompound according to claim 4 or a salt thereof, wherein: R¹ is C₁-C₈alkyl, halo, haloalkyl, haloalkoxy, —C(Y)NR^(b)R^(b′) or —OR^(d); andeach R^(b), R^(b′), R^(d) and R^(f) is independently hydrogen, C₁-C₈alkyl, C₃-C₈ cycloalkyl or haloalkyl.
 6. The compound according to claim1 or a salt thereof, wherein the compound of formula (I) is a compoundselected from the group consisting of:


7. A pharmaceutical composition comprising the compound according to anyone of claim 1 or claims 1-6 or a salt thereof as an active ingredientand a pharmaceutically acceptable carrier.